2-oxo-oxazolidin-3,5-diyl antibiotic derivatives

ABSTRACT

The invention relates to antibacterial compounds of formula I 
     
       
         
         
             
             
         
       
         
         wherein 
         R 1a  represents H or carboxy and R 1b  represents H, or R 1a  and R 1b  represent together either the group *—C(O)—NH—S— #  or the group *—C(OH)═N—S— #  wherein “*” represents the point of attachment of R 1a  and “ # ” represents the point of attachment of R 1b ; 
         R 2  represents H, (C 1 -C 3 )alkyl, hydroxy-(C 1 -C 3 )alkyl, benzyl or (C 3 -C 5 )cycloalkyl; 
         R 3  represents H or halogen; 
         U represents N or CR 4 ; wherein R 4  is H or (C 1 -C 3 )alkoxy; 
         A represents CH, B represents NH and m represents 1 or 2 and n represents 1 or 2; or A represents N, B is absent, m represents 2 and n represents 2; 
         Y represents CH or N; and 
         Q represents O or S;
       and salts of such compounds.

The present invention concerns 2-oxo-oxazolidin-3,5-diyl antibioticderivatives, a pharmaceutical antibacterial composition containing themand the use of these compounds in the manufacture of a medicament forthe treatment of infections (e.g. bacterial infections). These compoundsare useful antimicrobial agents effective against a variety of human andveterinary pathogens including among others Gram-positive andGram-negative aerobic and anaerobic bacteria and mycobacteria.

The intensive use of antibiotics has exerted a selective evolutionarypressure on microorganisms to produce genetically based resistancemechanisms. Modern medicine and socio-economic behaviour exacerbate theproblem of resistance development by creating slow growth situations forpathogenic microbes, e.g. in artificial joints, and by supportinglong-term host reservoirs, e.g. in immune-compromised patients.

In hospital settings, an increasing number of strains of Staphylococcusaureus, Streptococcus pneumoniae, Enterococcus spp., and Pseudomonasaeruginosa, major sources of infections, are becoming multi-drugresistant and therefore difficult if not impossible to treat:

-   -   S. aureus is resistant to β-lactams, quinolones and now even to        vancomycin;    -   S. pneumoniae is becoming resistant to penicillin or quinolone        antibiotics and even to new macrolides;    -   Enteroccocci are quinolone and vancomycin resistant and β-lactam        antibiotics are inefficacious against these strains;    -   Enterobacteriacea are cephalosporin and quinolone resistant;    -   P. aeruginosa are β-lactam and quinolone resistant.

Furthermore, the incidence of multi-drug-resistant Gram-negative strainssuch as Enterobacteriacae and Pseudomonas aeruginosa, is steadilyincreasing and new emerging organisms like Acinetobacter spp. orClostridium difficile, which have been selected during therapy with thecurrently used antibiotics, are becoming a real problem in hospitalsettings. Therefore, there is a high medical need for new antibacterialagents which overcome these multidrug-resistant bacilli.

In addition, microorganisms that are causing persistent infections areincreasingly being recognized as causative agents or cofactors of severechronic diseases like peptic ulcers or heart diseases.

WO 2006/024171 and US 2007/0060558 describe antibacterial compounds offormula (A1)

wherein

n and n′ each independently represent 0, 1, 2 or 3;

R_(1a) and R_(1b) can (notably) each independently represent halogen,(C₁-C₆)alkyl or (C₁-C₆)alkoxy;

R₂ can notably represent H and the group —(Y₁)_(p)—(U)_(p)—(Y₂)_(p″)—can notably represent 2-ethylamino, 2-propylamino or 3-propylamino, oralso R₂ can form a cyclic structure with Y₁, U or Y₂;

R₆ and R₇ can (among other possibilities) form together a cyclicstructure.

Besides, WO 2008/126034 describes antibacterial compounds of formula(A2)

wherein

R¹ represents hydrogen, alkoxy, halogen or cyano;

one or two of U, V, W, and X represent(s) N and the remaining eachrepresent CH, or, in the case of X, represent CR^(a), R^(a) representingH or halogen;

each of R², R³, R⁴ and R⁵ can notably represent H;

R⁶ represents H or (C₁-C₄)alkyl;

A, B, m, n, D and E can notably have the following respective meanings:

-   -   A represents N, B represents N, D represents a bond, E        represents CH₂ or *—COCH₂— wherein the asterisk indicates the        bond which is attached to B, and m and n each represent 1; or    -   A represents N, B represents C(OH), D represents a bond, E        represents CH₂, and m and n each represent 1; or    -   A represents N, B represents CH, D represents NR^(b), E        represents CH₂, R^(b) represents H or (C₁-C₄)alkyl, and m and n        each represent 1; or    -   A represents N, B represents CH, D represents NH, E represents        CH₂, m represents the integer 2, and n represents 0; or    -   A represents N, B represents CH, D represents NR^(c), E        represents CH₂, CO or CH₂CH₂, R^(c) represents H or        (C₁-C₄)alkyl, m represents 1, and n represents 0; or    -   A represents N, B represents CH, D represents        *—CH(R^(d))—N(R^(e))— wherein the asterisk indicates the bond        which is attached to B, E represents CH₂ or CO, R^(d) represents        H, R^(e) represents H or (C₁-C₄)alkyl, m represents 1, and n        represents 0; or    -   A represents N, B represents CH, D represents *—CONH— wherein        the asterisk indicates the bond which is attached to B, E        represents CH₂, m represents 1, and n represents 0; or    -   A represents N, B represents C(OH), D represents *—CH₂—NH—        wherein the asterisk indicates the bond which is attached to B,        E represents CH₂, m represents 1, and n represents 0; or    -   A represents N, B represents CH, D represents *—CO—NH— wherein        the asterisk indicates the bond which is attached to B, E        represents CH₂, and m and n each represent 0; or    -   A represents N, B represents CH, D represents *—CH₂—N(R^(f))—        wherein the asterisk indicates the bond which is attached to B,        E represents CH₂, CH₂CH₂ or CO, R^(f) represents H or        (C₁-C₄)alkyl, and m and n each represent 0; or    -   A represents N, B represents CH, D represents NR^(g), E        represents CH₂, CH₂CH₂, CO or *—COCH₂— wherein the asterisk        indicates the bond which is attached to B, R^(g) represents H,        (C₁-C₄)alkyl or (C₂-C₄)alkyl which is mono- or di-substituted        with hydroxy, and m and n each represent 0;

G may notably represent a group

wherein R^(h) represents H or fluorine, M represents CH or N and Q′represents O or S.

The instant invention provides further antibacterial compoundscomprising a 2-oxo-oxazolidin-3,5-diyl motif, i.e. the compounds offormula I described herein.

Various embodiments of the invention are presented hereafter:

1) The invention relates to the compounds of formula I

wherein

R^(1a) represents H or carboxy and R^(1b) represents H, or R^(1a) andR^(1b) represent together either the group *—C(O)—NH—S—^(#) or the group*—C(OH)═N—S—^(#) wherein “*” represents the point of attachment ofR^(1a) and “^(#)” represents the point of attachment of R^(1b);

R² represents H, (C₁-C₃)alkyl, hydroxy-(C₁-C₃)alkyl, benzyl or(C₃-C₅)cycloalkyl;

R³ represents H or halogen (especially fluorine);

U represents N or CR⁴, wherein R⁴ is H or (C₁-C₃)alkoxy;

A represents CH, B represents NH, m represents 1 or 2 and n represents 1or 2; or A represents N, B is absent (i.e. A is directly bound to theCH₂ group), m represents 2 and n represents 2;

Y represents CH or N; and

Q represents O or S.

2) The invention notably relates to the compounds of formula I accordingto embodiment 1) which are also compounds of formula I_(E1)

wherein the absolute configuration of the oxazolidinone moiety is asdepicted in formula I_(E1) [i.e. the absolute configuration of theoxazolidinone moiety is (R)].

3) The invention also notably relates to the compounds of formula Iaccording to embodiment 1) which are also compounds of formula I_(E2)

wherein the absolute configuration of the oxazolidinone moiety is asdepicted in formula I_(E2) [i.e. the absolute configuration of theoxazolidinone moiety is (S)].

4) The invention in particular relates to the compounds of formula Iaccording to embodiment 1) which are also compounds of formula I_(P)

wherein

R^(1a) represents H or carboxy;

R^(1b) represents H;

R² represents H, (C₁-C₃)alkyl, hydroxy-(C₁-C₃)alkyl, benzyl or(C₃-C₅)cycloalkyl;

R³ represents H or halogen (especially fluorine);

U represents N or CR⁴; wherein R⁴ is H or (C₁-C₃)alkoxy;

A represents CH, B represents NH and m represents 1 and n represent 1 orm represents 2 and n represents 2; or A represents N, B is absent (i.e.A is directly bound to the CH₂ group), m represents 2 and n represents2;

Y represents CH or N; and

Q represents O or S.

5) Another embodiment of the invention relates to the compounds offormula I_(P) according to embodiment 4) which are also compounds offormula I_(PE1)

wherein the absolute configuration of the oxazolidinone moiety is asdepicted in formula I_(E1) [i.e. the absolute configuration of theoxazolidinone moiety is (R)].

6) Yet another embodiment of the invention relates to the compounds offormula I_(P) according to embodiment 4) which are also compounds offormula I_(PE2)

wherein the absolute configuration of the oxazolidinone moiety is asdepicted in formula I_(PE2) [i.e. the absolute configuration of theoxazolidinone moiety is (S)].

The following paragraphs provide definitions of the various chemicalmoieties for the compounds according to the invention and are intendedto apply uniformly throughout the specification and claims, unless anotherwise expressly set out definition provides a broader or narrowerdefinition:

-   -   The term “alkyl”, used alone or in combination, refers to a        straight or branched chain alkyl group containing from one to        four carbon atoms. The term “(C₁-C_(x))alkyl” (x being an        integer) refers to a straight or branched chain alkyl group        containing 1 to x carbon atoms. For example, a (C₁-C₃)alkyl        group contains from one to three carbon atoms. Representative        examples of alkyl groups include methyl, ethyl, propyl,        iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl.        Preferred are methyl and ethyl.    -   The term “(C_(x)-C_(y))hydroxyalkyl” (each of x and y being an        integer) refers to a hydroxyalkyl group wherein the alkyl group        contains x to y carbon atoms. Representative examples of        (C₁-C₃)hydroxyalkyl groups include, but are not limited to,        hydroxymethyl, 2-hydroxy-ethyl, 1-hydroxy-ethyl and        3-hydroxy-propyl. Preferred (C₁-C₃)hydroxyalkyl groups are        2-hydroxy-ethyl and 3-hydroxy-propyl. Representative examples of        (C₂-C₃)hydroxyalkyl groups include, but are not limited to,        2-hydroxy-ethyl, 1-hydroxy-ethyl, 2-hydroxy-propyl and        3-hydroxy-propyl. Preferred (C₂-C₃)hydroxyalkyl groups are        2-hydroxy-ethyl and 3-hydroxy-propyl.    -   The term “cycloalkyl” refers to a saturated monocyclic group        with three to six carbon ring-atoms, for example cyclopropyl,        cyclobutyl, cyclopentyl, cyclohexyl. The term        “(C₃-C_(x))cycloalkyl” (x being an integer between 4 and 6)        refers to a saturated monocyclic group containing 3 to x carbon        atoms. For example, a (C₃-C₅)cycloalkyl group contains from        three to five carbon atoms. Any cycloalkyl group as defined        herein may be substituted with one, two halogen substituents in        particular fluorine. The term “cycloalkyl” preferably refers to        cyclopropyl.    -   The term “alkoxy” refers to a straight or branched chain alkoxy        group containing from one to four carbon atoms. The term        “(C_(x)-C_(y))alkoxy” (x and y each being an integer) refers to        an alkoxy group as defined before containing x to y carbon        atoms. For example, a (C₁-C₃)alkoxy group contains from one to        three carbon atoms. Representative examples of alkoxy groups        include methoxy, ethoxy, n-propoxy and iso-propoxy. Preferred        are methoxy and ethoxy. Most preferred is methoxy. For the        substituent R⁴ preferred is methoxy.    -   The term “halogen” refers to fluorine, chlorine, bromine or        iodine, and preferably to fluorine or chlorine.    -   The term “carboxy” refers to the group —COOH.

7) A further embodiment of the present invention relates to compounds offormula I according to any one of embodiments 1) to 6) wherein R^(1a)represents carboxy and R^(1b) represents H, or R^(1a) and R^(1b)represent together either the group *—C(O)—NH—S—^(#) or the group*—C(OH)═N—S—^(#) wherein “*” represents the point of attachment ofR^(1a) and “^(#)” represents the point of attachment of R.

8) According to one variant of embodiment 7), the compounds of formula Iaccording to embodiment 7) will be such that R^(1a) represents carboxyand R^(1b) represents H.

9) According to the other variant of embodiment 7), the compounds offormula I according to embodiment 7) will be such that R^(1a) and R^(1b)represent together either the group *—C(O)—NH—S—^(#) or the group*—C(OH)═N—S—^(#) wherein “*” represents the point of attachment ofR^(1a) and “^(#)” represents the point of attachment of R^(1b).

10) A further embodiment of the present invention relates to compoundsof formula I according to any one of embodiments 1) to 9) wherein R²represents H, (C₁-C₃)alkyl, hydroxy-(C₂-C₃)alkyl, benzyl or(C₃-C₅)cycloalkyl.

11) According to one variant of embodiment 10), the compounds of formulaI according to embodiment 10) will be such that R² represents(C₁-C₃)alkyl or (C₃-C₅)cycloalkyl (especially cyclopropyl).

12) According to another variant of embodiment 10), the compounds offormula I according to embodiment 10) will be such that R² representsbenzyl.

13) According to yet another variant of embodiment 10), the compounds offormula I according to embodiment 10) will be such that R² representscyclopropyl.

14) A further embodiment of the present invention relates to compoundsof formula I according to any one of embodiments 1) to 13) wherein R³represents halogen (especially fluorine).

15) A further embodiment of the present invention relates to compoundsof formula I according to any one of embodiments 1) to 14) wherein Urepresents N.

16) A further embodiment of the present invention relates to compoundsof formula I according to any one of embodiments 1) to 14) wherein Urepresents CR⁴ wherein R⁴ is H or (C₁-C₃)alkoxy (especially H).

17) A further embodiment of the present invention relates to thecompounds of formula I according to any one of embodiments 1) to 3), orto the compounds of formula I as defined in any of embodiments 1) to 3)taken together with any of embodiments 7) to 16), wherein the group

is selected from the groups

wherein the asterisks denote the bond linking said groups to the CH₂group which is attached to the oxazolidinone moiety.

18) According to a particular variant of embodiment 17), the compoundsof formula I according to embodiment 17) will be such that the group

is the group

wherein the asterisk denotes the bond linking said group to the CH₂group which is attached to the oxazolidinone moiety.

19) A further embodiment of the present invention relates to thecompounds of formula I according to any one of embodiment 4) to 6), orto the compounds of formula I as defined in any of embodiments 4) to 6)taken together with any of embodiments 7) to 16), wherein the group

is selected from the groups

(and especially from the groups

wherein the asterisks denote the bond linking said groups to the CH₂group which is attached to the oxazolidinone moiety.

20) Yet a further embodiment of the present invention relates to thecompounds of formula I as defined in any of embodiments 1) to 3), or tothe compounds of formula I as defined in any of embodiments 1) to 3)taken together with any of embodiments 7) to 16), wherein A representsCH, B represents NH, m represents 1 or 2 and n represents 1 or 2.

21) According to one variant of embodiment 20), the compounds of formulaI according to embodiment 20) will be such that A represents CH, Brepresents NH, m represents 1 and n represents 1.

22) According to another variant of embodiment 20), the compounds offormula I according to embodiment 20) will be such that A represents CH,B represents NH, m represents 1 and n represents 2.

23) According to yet another variant of embodiment 20), the compounds offormula I according to embodiment 20) will be such that A represents CH,B represents NH, m represents 2 and n represents 2.

24) A further embodiment of the present invention relates to thecompounds of formula I according to any one of embodiments 4) to 6), oraccording to any one of embodiments 4) to 6) taken together with any oneof embodiments 8) and 11) to 16), wherein A represents CH, B representsNH and each of m and n represents 1.

25) A further embodiment of the present invention relates to thecompounds of formula I according to any one of embodiments 4) to 6), oraccording to any one of embodiments 4) to 6) taken together with any oneof embodiments 8) and 11) to 16), wherein A represents N, B is absentand each of m and n represents 2.

26) A further embodiment of the present invention relates to thecompounds of formula I according to any one of embodiments 4) to 6), oraccording to any one of embodiments 4) to 6) taken together with any oneof embodiments 8) and 11) to 16), wherein A represents CH, B is NH andeach of m and n represents 2.

27) A further embodiment of the present invention relates to thecompounds of formula I according to any one of embodiments 1) to 26)wherein Y represents CH or N and Q represents O, or Y represents CH andQ represents S.

28) A further embodiment of the present invention relates to thecompounds of formula I according to any one of embodiments 1) to 26)wherein Y represents N and Q represents O, or Y represents CH and Qrepresents S.

29) A particular embodiment of the present invention relates to thecompounds of formula I according to any of embodiments 1) to 3),wherein:

-   -   R^(1a) represents carboxy and R^(1b) represents H, or R^(1a) and        R^(1b) represent together either the group *—C(O)—NH—S—^(#) or        the group *—C(OH)═N—S—^(#) wherein “*” represents the point of        attachment of R^(1a) and “^(#)” represents the point of        attachment of R^(1b);    -   R² represents cyclopropyl;    -   R³ represents fluorine;    -   U represents N;    -   A represents CH, B represents NH, m represents 1 or 2 and n        represents 1 or 2;    -   Y represents N; and    -   Q represents O.

30) According to a main variant of this invention, the compounds offormula I as defined in embodiment 1) will also be compounds of formulaI₂

wherein

R^(1a) represents H or carboxy and R^(1b) represents H;

R² represents H, (C₁-C₃)alkyl, hydroxy-(C₁-C₃)alkyl, benzyl or(C₃-C₅)cycloalkyl;

R³ represents H or halogen (especially fluorine);

U represents N or CR⁴, wherein R⁴ is H or (C₁-C₃)alkoxy;

A represents CH, B represents NH, m represents 1 or 2 and n represents 1or 2; or A represents N, B is absent (i.e. A is directly bound to theCH₂ group), m represents 2 and n represents 2;

Y represents CH or N; and

Q represents O or S.

31) A particular embodiment of the present invention relates to thecompounds of formula I according to embodiment 30), wherein:

-   -   R^(1a) represents carboxy and R^(1b) represents H;    -   R² represents cyclopropyl;    -   R³ represents fluorine;    -   U represents N;    -   A represents CH, B represents NH, m represents 1 or 2 and n        represents 1 or 2;    -   Y represents N; and    -   Q represents O.

32) According to another main variant of this invention, the compoundsof formula I as defined in embodiment 1) will also be compounds offormula I₃ or I₃′

wherein

R² represents H, (C₁-C₃)alkyl, hydroxy-(C₁-C₃)alkyl, benzyl or(C₃-C₅)cycloalkyl;

R³ represents H or halogen (especially fluorine);

U represents N or CR⁴, wherein R⁴ is H or (C₁-C₃)alkoxy;

A represents CH, B represents NH, m represents 1 or 2 and n represents 1or 2; or A represents N, B is absent (i.e. A is directly bound to theCH₂ group), m represents 2 and n represents 2;

Y represents CH or N; and

Q represents O or S.

33) A particular embodiment of the present invention relates to thecompounds of formula I according to embodiment 32), wherein:

-   -   R² represents cyclopropyl;    -   R³ represents fluorine;    -   U represents N;    -   A represents CH, B represents NH, m represents 1 or 2 and n        represents 1 or 2;    -   Y represents N; and    -   Q represents O.

34) A further embodiment of the present invention relates to compoundsof formula I according to embodiment 1) or 4), which are selected fromthe group consisting of:

-   1-cyclopropyl-6-fluoro-4-oxo-7-{4-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]-piperazin-1-yl}-1,4-dihydro-quinoline-3-carboxylic    acid;-   1-cyclopropyl-6-fluoro-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylic    acid;-   1-cyclopropyl-6-fluoro-4-oxo-7-{4-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]-piperazin-1-yl}-1,4-dihydro-quinoline-3-carboxylic    acid;-   1-cyclopropyl-6-fluoro-4-oxo-7-{4-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]-piperazin-1-yl}-1,4-dihydro-[1,8]naphthyridine-3-carboxylic    acid;-   6-((R)-5-{[1-(8-cyclopropyl-3-fluoro-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-yl)-azetidin-3-ylamino]-methyl}-2-oxo-oxazolidin-3-yl)-4H-benzo[1,4]thiazin-3-one;-   1-cyclopropyl-6-fluoro-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylic    acid;-   1-cyclopropyl-8-methoxy-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-quinoline-3-carboxylic    acid;-   1-cyclopropyl-8-methoxy-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-quinoline-3-carboxylic    acid;-   1-ethyl-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylic    acid;-   1-cyclopropyl-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylic    acid;-   1-methyl-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylic    acid;-   6-fluoro-1-methyl-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylic    acid;-   1-benzyl-6-fluoro-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylic    acid;-   1-cyclopropyl-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylic    acid;-   6-fluoro-1-(2-hydroxy-ethyl)-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylic    acid;-   1-cyclopropyl-6-fluoro-4-oxo-7-{4-[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]-piperazin-1-yl}-1,4-dihydro-[1,8]naphthyridine-3-carboxylic    acid;-   1-cyclopropyl-6-fluoro-4-oxo-7-(4-{[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-piperidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylic    acid; and-   1-cyclopropyl-6-fluoro-4-oxo-7-{4-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-piperazin-1-yl}-1,4-dihydro-[1,8]naphthyridine-3-carboxylic    acid.

35) Yet a further embodiment of the present invention relates tocompounds of formula I according to embodiment 1), which are selectedfrom the group consisting of:

-   1-cyclopropyl-6-fluoro-4-oxo-7-{4-[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-piperazin-1-yl}-1,4-dihydro-[1,8]naphthyridine-3-carboxylic    acid;-   1-cyclopropyl-6-fluoro-4-oxo-7-(4-{[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-piperidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylic    acid;-   1-cyclopropyl-6-fluoro-4-oxo-7-(3-{[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-pyrrolidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylic    acid;-   1-cyclopropyl-6-fluoro-4-oxo-7-[(S)-3-{[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-methyl)-pyrrolidin-1-yl]-1,4-dihydro-[1,8]naphthyridine-3-carboxylic    acid;-   9-cyclopropyl-6-fluoro-3-hydroxy-7-(4-{[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-piperidin-1-yl)-9H-1-thia-2,8,9-triaza-cyclopenta[b]naphthalen-4-one;-   9-cyclopropyl-6-fluoro-3-hydroxy-7-(3-{[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-9H-1-thia-2,8,9-triaza-cyclopenta[b]naphthalen-4-one;    and-   9-cyclopropyl-6-fluoro-3-hydroxy-7-{4-[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-piperazin-1-yl}-9H-1-thia-2,8,9-triaza-cyclopenta[b]naphthalen-4-one.

36) The invention furthermore relates to the groups of compounds offormula I selected from the group consisting of the compounds listed inembodiments 34) and 35), which groups of compounds furthermorecorrespond to one of embodiments 2) to 33), as well as to the salts (inparticular the pharmaceutically acceptable salts) of such compounds.

37) The invention moreover relates to any individual compound of formulaI selected from the group consisting of the compounds listed inembodiments 34) and 35), and to the salts (in particular thepharmaceutically acceptable salts) of such individual compound.

Where the plural form is used for compounds, salts, pharmaceuticalcompositions, diseases or the like, this is intended to mean also asingle compound, salt, disease or the like.

Any reference to compounds of formula I, I_(E1), I_(E2), I_(O), I_(PE1),I_(PE2), I₂, I₃ and I₃′ is to be understood as referring also to thesalts, especially the pharmaceutically acceptable salts of suchcompounds, as appropriate and expedient.

The term “pharmaceutically acceptable salts” refers to non-toxic,inorganic or organic acid and/or base addition salts. Reference can bemade to “Salt selection for basic drugs”, Int. J. Pharm. (1986), 33,201-217.

Besides, the term “room temperature” as used herein refers to atemperature of 25° C.

Unless used regarding temperatures, the term “about” placed before anumerical value “X” refers in the current application to an intervalextending from X minus 10% of X to X plus 10% of X, and preferably to aninterval extending from X minus 5% of X to X plus 5% of X. In theparticular case of temperatures, the term “about” placed before atemperature “Y” refers in the current application to an intervalextending from the temperature Y minus 10° C. to Y plus 10° C., andpreferably to an interval extending from Y minus 5° C. to Y plus 5° C.

Whenever the word “between” is used to describe a numerical range, it isto be understood that the end points of the indicated range areexplicitly included in the range. For example: if a temperature range isdescribed to be between 40° C. and 80° C., this means that the endpoints 40° C. and 80° C. are included in the range; or if a variable isdefined as being an integer between 1 and 4, this means that thevariable is the integer 1, 2, 3, or 4.

The present invention also includes isotope labeled, especially ²H(deuterium) labeled compounds of formula I as defined in any one ofembodiments 1) to 36), which compounds are identical to the compounds offormula I except that one or more atoms have each been replaced by anatom having the same atomic number but an atomic mass different from theatomic mass usually found in nature. Isotope labeled, especially ²H(deuterium) labeled compounds of formula I and salts thereof are withinthe scope of the present invention. Substitution of hydrogen with theheavier isotope ²H (deuterium) may lead to greater metabolic stability,resulting e.g. in increased in-vivo half-life or reduced dosagerequirements, or may lead to reduced inhibition of cytochrome P450enzymes, resulting e.g. in an improved safety profile. In one embodimentof the invention, the compounds of formula I are not isotope labeled, orthey are labeled only with one or more deuterium atoms. In asub-embodiment, the compounds of formula I are not isotope labeled atall. Isotope labeled compounds of formula I may be prepared in analogyto the methods described hereinafter, but using the appropriate isotopevariation of suitable reagents or starting materials.

The compounds of formula I and their pharmaceutically acceptable saltscan be used as medicaments, e.g. in the form of pharmaceuticalcompositions for enteral (such especially oral) or parenteraladministration (including topical application or inhalation).

In a preferred embodiment of the invention, the administered amount ofcompound of formula I will be comprised between 1 mg and 1000 mg perday, particularly between 5 mg and 500 mg per day, more particularlybetween 25 mg and 400 mg per day, especially between 50 mg and 200 mgper day.

A further aspect of the invention are pharmaceutical compositionscomprising a compound of formula I, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable excipient/carriermaterial.

The production of the pharmaceutical compositions can be effected in amanner which will be familiar to any person skilled in the art (see forexample Mark Gibson, Editor, Pharmaceutical Preformulation andFormulation, IHS Health Group, Englewood, Colo., USA, 2001; Remington,The Science and Practice of Pharmacy, 20th Edition, Philadelphia Collegeof Pharmacy and Science) by bringing the described compounds of formulaI and their pharmaceutically acceptable salts, optionally in combinationwith other therapeutically valuable substances, into a galenicaladministration form together with suitable, non-toxic, inert,therapeutically compatible solid or liquid carrier materials and, ifdesired, usual pharmaceutical adjuvants.

The compounds of formula I according to the invention, i.e. according toany one of embodiments 1) to 37) above, are suitable for the use aschemotherapeutic active compounds in human and veterinary medicine andas substances for preserving inorganic and organic materials inparticular all types of organic materials for example polymers,lubricants, paints, fibres, leather, paper and wood.

The compounds of formula I according to any one of embodiments 1) to 37)are particularly active against bacteria and bacteria-like organisms.They may therefore be particularly suitable in human and veterinarymedicine for the prophylaxis and chemotherapy of local and systemicinfections caused by these pathogens as well as disorders related tobacterial infections comprising pneumonia, otitis media, sinusitis,bronchitis, tonsillitis, and mastoiditis related to infection byStreptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis,Staphylococcus aureus, Enterococcus faecalis, E. faecium, E.casseliflavus, S. epidermidis, S. haemolyticus, or Peptostreptococcusspp.; pharyngitis, rheumatic fever, and glomerulonephritis related toinfection by Streptococcus pyogenes, Groups C and G streptococci,Corynebacterium diphtheriae, or Actinobacillus haemolyticum; respiratorytract infections related to infection by Mycoplasma pneumoniae,Legionella pneumophila, Streptococcus pneumoniae, Haemophilusinfluenzae, or Chlamydia pneumoniae; blood and tissue infections,including endocarditis and osteomyelitis, caused by S. aureus, S.haemolyticus, E. faecalis, E. faecium, E. durans, including strainsresistant to known antibacterials such as, but not limited to,beta-lactams, vancomycin, aminoglycosides, quinolones, chloramphenicol,tetracyclines and macrolides; uncomplicated skin and soft tissueinfections and abscesses, and puerperal fever related to infection byStaphylococcus aureus, coagulase-negative staphylococci (i.e., S.epidermidis, S. haemolyticus, etc.), Streptococcus pyogenes,Streptococcus agalactiae, Streptococcal groups C-F (minute colonystreptococci), viridans streptococci, Corynebacterium minutissimum,Clostridium spp., or Bartonella henselae; uncomplicated acute urinarytract infections related to infection by Staphylococcus aureus,coagulase-negative staphylococcal species, or Enterococcus spp.;urethritis and cervicitis; sexually transmitted diseases related toinfection by Chlamydia trachomatis, Haemophilus ducreyi, Treponemapallidum, Ureaplasma urealyticum, or Neiserria gonorrheae; toxindiseases related to infection by S. aureus (food poisoning and toxicshock syndrome), or Groups A, B, and C streptococci; ulcers related toinfection by Helicobacter pylori; systemic febrile syndromes related toinfection by Borrelia recurrentis; Lyme disease related to infection byBorrelia burgdorferi; conjunctivitis, keratitis, and dacrocystitisrelated to infection by Chlamydia trachomatis, Neisseria gonorrhoeae, S.aureus, S. pneumoniae, S. pyogenes, H. influenzae, or Listeria spp.;disseminated Mycobacterium avium complex (MAC) disease related toinfection by Mycobacterium avium, or Mycobacterium intracellulare;infections caused by Mycobacterium tuberculosis, M. leprae, M.paratuberculosis, M. kansasii, or M. chelonei; gastroenteritis relatedto infection by Campylobacter jejuni; intestinal protozoa related toinfection by Cryptosporidium spp.; odontogenic infection related toinfection by viridans streptococci; persistent cough related toinfection by Bordetella pertussis; gas gangrene related to infection byClostridium perfringens or Bacteroides spp.; and atherosclerosis orcardiovascular disease related to infection by Helicobacter pylori orChlamydia pneumoniae.

The compounds of formula I according to any one of embodiments 1) to37), or the pharmaceutically acceptable salt thereof, may be used forthe preparation of a medicament, and are suitable, for the prevention ortreatment of a bacterial infection.

Accordingly, the compounds of formula I according to any one ofembodiments 1) to 37), or the pharmaceutically acceptable salts thereof,may be used for the preparation of a medicament, and are suitable, forthe prevention or treatment of a bacterial infection selected from thegroup consisting of respiratory tract infections, otitis media,meningitis, skin and soft tissue infections (whether complicated oruncomplicated), pneumonia (including hospital acquired pneumonia),bacteremia, endocarditis, intraabdominal infections, gastrointestinalinfections, Clostridium difficile infections, urinary tract infections,sexually transmitted infections, foreign body infections, osteomyelitis,lyme disease, topical infections, opthalmological infections,tuberculosis and tropical diseases (e.g. malaria), and notably for theprevention or treatment of a bacterial infection selected from the groupconsisting of respiratory tract infections, otitis media, meningitis,skin and soft tissue infections (whether complicated or uncomplicated),pneumonia (including hospital acquired pneumonia) and bacteremia.

The compounds of formula I according to any one of embodiments 1) to 37)may further be useful for the preparation of a medicament, and aresuitable, for the treatment of infections that are mediated by Gramnegative bacteria, such as E. coli, Klebsiella pneumoniae and otherEnterobacteriaceae, Acinetobacter spp. including Acinetobacter baumanii,Pseudomonas aeruginiosa, Stenotrophomonas maltophilia, Neisseriameningitidis, and Bacteroides spp.

The compounds of formula I according to any one of embodiments 1) to 37)may further be useful for the preparation of a medicament, and aresuitable, for the treatment of infections that are mediated by Grampositive bacteria such as Bacillus cereus, Bacillus anthracis,Clostridium difficile, Corynebacterium spp. and Propionibacterium acnes.

The compounds of formula I according to any one of embodiments 1) to 37)may further be useful for the preparation of a medicament, and aresuitable, for the treatment of protozoal infections caused by Plasmodiummalaria, Plasmodium falciparum, Toxoplasma gondii, Pneumocystis carinii,Trypanosoma brucei and Leishmania spp.

The present list of pathogens is to be interpreted merely as examplesand in no way as limiting.

One aspect of this invention therefore relates to the use of a compoundof formula I according to any one of embodiments 1) to 37), or of apharmaceutically acceptable salt thereof, for the manufacture of amedicament for the prevention or treatment of a bacterial infection.Another aspect of this invention relates to a compound of formula Iaccording to any one of embodiments 1) to 37), or of a pharmaceuticallyacceptable salt thereof, for the prevention or treatment of a bacterialinfection (in particular for the prevention or treatment of a bacterialinfection caused by Staphylococcus aureus or Acinetobacter baumaniibacteria, and notably caused by quinolone-resistant Staphylococcusaureus or Acinetobacter baumanii bacteria).

Another aspect of the invention concerns a method for the prevention orthe treatment of an infection as detailed above (and in particular forthe prevention or treatment of a bacterial infection caused byStaphylococcus aureus or Acinetobacter baumanii bacteria, and notablycaused by quinolone-resistant Staphylococcus aureus or Acinetobacterbaumanii bacteria) in a patient comprising the administration to saidpatient of a pharmaceutically active amount of a compound of formula Iaccording to one of embodiments 1) to 37) or a pharmaceuticallyacceptable salt thereof.

As well as in humans, bacterial infections can also be treated usingcompounds of formula I (or pharmaceutically acceptable salts thereof) inother species like pigs, ruminants, horses, dogs, cats and poultry.

This invention, thus, relates to the compounds of formula I as definedin embodiment 1), or further limited under consideration of theirrespective dependencies by the characteristics of any one of embodiments2) to 37), and to pharmaceutically acceptable salts thereof. It relatesfurthermore to the use of such compounds as medicaments, especially forthe prevention or treatment of a bacterial infection, in particular forthe prevention or treatment of a bacterial infection caused byStaphylococcus aureus or Acinetobacter baumanii bacteria, and notablycaused by quinolone-resistant Staphylococcus aureus or Acinetobacterbaumanii bacteria. The following embodiments relating to the compoundsof formula I according to embodiment 1) are thus possible and intendedand herewith specifically disclosed in individualized form:

7+1, 7+2, 7+3, 7+4, 7+5, 7+6, 8+7+1, 8+7+2, 8+7+3, 8+7+4, 8+7+5, 8+7+6,9+7+1, 9+7+2, 9+7+3, 9+7+4, 9+7+5, 9+7+6, 10+1, 10+2, 10+3, 10+4, 10+5,10+6, 10+7+1, 10+7+2, 10+7+3, 10+7+4, 10+7+5, 10+7+6, 10+8+7+1,10+8+7+2, 10+8+7+3, 10+8+7+4, 10+8+7+5, 10+8+7+6, 10+9+7+1, 10+9+7+2,10+9+7+3, 10+9+7+4, 10+9+7+5, 10+9+7+6, 11+10+1, 11+10+2, 11+10+3,11+10+4, 11+10+5, 11+10+6, 11+10+7+1, 11+10+7+2, 11+10+7+3, 11+10+7+4,11+10+7+5, 11+10+7+6, 11+10+8+7+1, 11+10+8+7+2, 11+10+8+7+3,11+10+8+7+4, 11+10+8+7+5, 11+10+8+7+6, 11+10+9+7+1, 11+10+9+7+2,11+10+9+7+3, 11+10+9+7+4, 11+10+9+7+5, 11+10+9+7+6, 12+10+1, 12+10+2,12+10+3, 12+10+4, 12+10+5, 12+10+6, 12+10+7+1, 12+10+7+2, 12+10+7+3,12+10+7+4, 12+10+7+5, 12+10+7+6, 12+10+8+7+1, 12+10+8+7+2, 12+10+8+7+3,12+10+8+7+4, 12+10+8+7+5, 12+10+8+7+6, 12+10+9+7+1, 12+10+9+7+2,12+10+9+7+3, 12+10+9+7+4, 12+10+9+7+5, 12+10+9+7+6, 13+10+1, 13+10+2,13+10+3, 13+10+4, 13+10+5, 13+10+6, 13+10+7+1, 13+10+7+2, 13+10+7+3,13+10+7+4, 13+10+7+5, 13+10+7+6, 13+10+8+7+1, 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36+28+15+13+10+9+7+6,36+28+15+14+1, 36+28+15+14+2, 36+28+15+14+3, 36+28+15+14+4,36+28+15+14+5, 36+28+15+14+6, 36+28+15+14+7+1, 36+28+15+14+7+2,36+28+15+14+7+3, 36+28+15+14+7+4, 36+28+15+14+7+5, 36+28+15+14+7+6,36+28+15+14+8+7+1, 36+28+15+14+8+7+2, 36+28+15+14+8+7+3,36+28+15+14+8+7+4, 36+28+15+14+8+7+5, 36+28+15+14+8+7+6,36+28+15+14+9+7+1, 36+28+15+14+9+7+2, 36+28+15+14+9+7+3,36+28+15+14+9+7+4, 36+28+15+14+9+7+5, 36+28+15+14+9+7+6,36+28+15+14+10+1, 36+28+15+14+10+2, 36+28+15+14+10+3, 36+28+15+14+10+4,36+28+15+14+10+5, 36+28+15+14+10+6, 36+28+15+14+10+7+1,36+28+15+14+10+7+2, 36+28+15+14+10+7+3, 36+28+15+14+10+7+4,36+28+15+14+10+7+5, 36+28+15+14+10+7+6, 36+28+15+14+10+8+7+1,36+28+15+14+10+8+7+2, 36+28+15+14+10+8+7+3, 36+28+15+14+10+8+7+4,36+28+15+14+10+8+7+5, 36+28+15+14+10+8+7+6, 36+28+15+14+10+9+7+1,36+28+15+14+10+9+7+2, 36+28+15+14+10+9+7+3, 36+28+15+14+10+9+7+4,36+28+15+14+10+9+7+5, 36+28+15+14+10+9+7+6, 36+28+15+14+11+10+1,36+28+15+14+11+10+2, 36+28+15+14+11+10+3, 36+28+15+14+11+10+4,36+28+15+14+11+10+5, 36+28+15+14+11+10+6, 36+28+15+14+11+10+7+1,36+28+15+14+11+10+7+2, 36+28+15+14+11+10+7+3, 36+28+15+14+11+10+7+4,36+28+15+14+11+10+7+5, 36+28+15+14+11+10+7+6, 36+28+15+14+11+10+8+7+1,36+28+15+14+11+10+8+7+2, 36+28+15+14+11+10+8+7+3,36+28+15+14+11+10+8+7+4, 36+28+15+14+11+10+8+7+5,36+28+15+14+11+10+8+7+6, 36+28+15+14+11+10+9+7+1,36+28+15+14+11+10+9+7+2, 36+28+15+14+11+10+9+7+3,36+28+15+14+11+10+9+7+4, 36+28+15+14+11+10+9+7+5,36+28+15+14+11+10+9+7+6, 36+28+15+14+12+10+1, 36+28+15+14+12+10+2,36+28+15+14+12+10+3, 36+28+15+14+12+10+4, 36+28+15+14+12+10+5,36+28+15+14+12+10+6, 36+28+15+14+12+10+7+1, 36+28+15+14+12+10+7+2,36+28+15+14+12+10+7+3, 36+28+15+14+12+10+7+4, 36+28+15+14+12+10+7+5,36+28+15+14+12+10+7+6, 36+28+15+14+12+10+8+7+1, 36+28+15+14+12+10+8+7+2,36+28+15+14+12+10+8+7+3, 36+28+15+14+12+10+8+7+4,36+28+15+14+12+10+8+7+5, 36+28+15+14+12+10+8+7+6,36+28+15+14+12+10+9+7+1, 36+28+15+14+12+10+9+7+2,36+28+15+14+12+10+9+7+3, 36+28+15+14+12+10+9+7+4,36+28+15+14+12+10+9+7+5, 36+28+15+14+12+10+9+7+6, 36+28+15+14+13+10+1,36+28+15+14+13+10+2, 36+28+15+14+13+10+3, 36+28+15+14+13+10+4,36+28+15+14+13+10+5, 36+28+15+14+13+10+6, 36+28+15+14+13+10+7+1,36+28+15+14+13+10+7+2, 36+28+15+14+13+10+7+3, 36+28+15+14+13+10+7+4,36+28+15+14+13+10+7+5, 36+28+15+14+13+10+7+6, 36+28+15+14+13+10+8+7+1,36+28+15+14+13+10+8+7+2, 36+28+15+14+13+10+8+7+3,36+28+15+14+13+10+8+7+4, 36+28+15+14+13+10+8+7+5,36+28+15+14+13+10+8+7+6, 36+28+15+14+13+10+9+7+1,36+28+15+14+13+10+9+7+2, 36+28+15+14+13+10+9+7+3,36+28+15+14+13+10+9+7+4, 36+28+15+14+13+10+9+7+5,36+28+15+14+13+10+9+7+6, 36+28+16+1, 36+28+16+2, 36+28+16+3, 36+28+16+4,36+28+16+5, 36+28+16+6, 36+28+16+7+1, 36+28+16+7+2, 36+28+16+7+3,36+28+16+7+4, 36+28+16+7+5, 36+28+16+7+6, 36+28+16+8+7+1,36+28+16+8+7+2, 36+28+16+8+7+3, 36+28+16+8+7+4, 36+28+16+8+7+5,36+28+16+8+7+6, 36+28+16+9+7+1, 36+28+16+9+7+2, 36+28+16+9+7+3,36+28+16+9+7+4, 36+28+16+9+7+5, 36+28+16+9+7+6, 36+28+16+10+1,36+28+16+10+2, 36+28+16+10+3, 36+28+16+10+4, 36+28+16+10+5,36+28+16+10+6, 36+28+16+10+7+1, 36+28+16+10+7+2, 36+28+16+10+7+3,36+28+16+10+7+4, 36+28+16+10+7+5, 36+28+16+10+7+6, 36+28+16+10+8+7+1,36+28+16+10+8+7+2, 36+28+16+10+8+7+3, 36+28+16+10+8+7+4,36+28+16+10+8+7+5, 36+28+16+10+8+7+6, 36+28+16+10+9+7+1,36+28+16+10+9+7+2, 36+28+16+10+9+7+3, 36+28+16+10+9+7+4,36+28+16+10+9+7+5, 36+28+16+10+9+7+6, 36+28+16+11+10+1,36+28+16+11+10+2, 36+28+16+11+10+3, 36+28+16+11+10+4, 36+28+16+11+10+5,36+28+16+11+10+6, 36+28+16+11+10+7+1, 36+28+16+11+10+7+2,36+28+16+11+10+7+3, 36+28+16+11+10+7+4, 36+28+16+11+10+7+5,36+28+16+11+10+7+6, 36+28+16+11+10+8+7+1, 36+28+16+11+10+8+7+2,36+28+16+11+10+8+7+3, 36+28+16+11+10+8+7+4, 36+28+16+11+10+8+7+5,36+28+16+11+10+8+7+6, 36+28+16+11+10+9+7+1, 36+28+16+11+10+9+7+2,36+28+16+11+10+9+7+3, 36+28+16+11+10+9+7+4, 36+28+16+11+10+9+7+5,36+28+16+11+10+9+7+6, 36+28+16+12+10+1, 36+28+16+12+10+2,36+28+16+12+10+3, 36+28+16+12+10+4, 36+28+16+12+10+5, 36+28+16+12+10+6,36+28+16+12+10+7+1, 36+28+16+12+10+7+2, 36+28+16+12+10+7+3,36+28+16+12+10+7+4, 36+28+16+12+10+7+5, 36+28+16+12+10+7+6,36+28+16+12+10+8+7+1, 36+28+16+12+10+8+7+2, 36+28+16+12+10+8+7+3,36+28+16+12+10+8+7+4, 36+28+16+12+10+8+7+5, 36+28+16+12+10+8+7+6,36+28+16+12+10+9+7+1, 36+28+16+12+10+9+7+2, 36+28+16+12+10+9+7+3,36+28+16+12+10+9+7+4, 36+28+16+12+10+9+7+5, 36+28+16+12+10+9+7+6,36+28+16+13+10+1, 36+28+16+13+10+2, 36+28+16+13+10+3, 36+28+16+13+10+4,36+28+16+13+10+5, 36+28+16+13+10+6, 36+28+16+13+10+7+1,36+28+16+13+10+7+2, 36+28+16+13+10+7+3, 36+28+16+13+10+7+4,36+28+16+13+10+7+5, 36+28+16+13+10+7+6, 36+28+16+13+10+8+7+1,36+28+16+13+10+8+7+2, 36+28+16+13+10+8+7+3, 36+28+16+13+10+8+7+4,36+28+16+13+10+8+7+5, 36+28+16+13+10+8+7+6, 36+28+16+13+10+9+7+1,36+28+16+13+10+9+7+2, 36+28+16+13+10+9+7+3, 36+28+16+13+10+9+7+4,36+28+16+13+10+9+7+5, 36+28+16+13+10+9+7+6, 36+28+16+14+1,36+28+16+14+2, 36+28+16+14+3, 36+28+16+14+4, 36+28+16+14+5,36+28+16+14+6, 36+28+16+14+7+1, 36+28+16+14+7+2, 36+28+16+14+7+3,36+28+16+14+7+4, 36+28+16+14+7+5, 36+28+16+14+7+6, 36+28+16+14+8+7+1,36+28+16+14+8+7+2, 36+28+16+14+8+7+3, 36+28+16+14+8+7+4,36+28+16+14+8+7+5, 36+28+16+14+8+7+6, 36+28+16+14+9+7+1,36+28+16+14+9+7+2, 36+28+16+14+9+7+3, 36+28+16+14+9+7+4,36+28+16+14+9+7+5, 36+28+16+14+9+7+6, 36+28+16+14+10+1,36+28+16+14+10+2, 36+28+16+14+10+3, 36+28+16+14+10+4, 36+28+16+14+10+5,36+28+16+14+10+6, 36+28+16+14+10+7+1, 36+28+16+14+10+7+2,36+28+16+14+10+7+3, 36+28+16+14+10+7+4, 36+28+16+14+10+7+5,36+28+16+14+10+7+6, 36+28+16+14+10+8+7+1, 36+28+16+14+10+8+7+2,36+28+16+14+10+8+7+3, 36+28+16+14+10+8+7+4, 36+28+16+14+10+8+7+5,36+28+16+14+10+8+7+6, 36+28+16+14+10+9+7+1, 36+28+16+14+10+9+7+2,36+28+16+14+10+9+7+3, 36+28+16+14+10+9+7+4, 36+28+16+14+10+9+7+5,36+28+16+14+10+9+7+6, 36+28+16+14+11+10+1, 36+28+16+14+11+10+2,36+28+16+14+11+10+3, 36+28+16+14+11+10+4, 36+28+16+14+11+10+5,36+28+16+14+11+10+6, 36+28+16+14+11+10+7+1, 36+28+16+14+11+10+7+2,36+28+16+14+11+10+7+3, 36+28+16+14+11+10+7+4, 36+28+16+14+11+10+7+5,36+28+16+14+11+10+7+6, 36+28+16+14+11+10+8+7+1, 36+28+16+14+11+10+8+7+2,36+28+16+14+11+10+8+7+3, 36+28+16+14+11+10+8+7+4,36+28+16+14+11+10+8+7+5, 36+28+16+14+11+10+8+7+6,36+28+16+14+11+10+9+7+1, 36+28+16+14+11+10+9+7+2,36+28+16+14+11+10+9+7+3, 36+28+16+14+11+10+9+7+4,36+28+16+14+11+10+9+7+5, 36+28+16+14+11+10+9+7+6, 36+28+16+14+12+10+1,36+28+16+14+12+10+2, 36+28+16+14+12+10+3, 36+28+16+14+12+10+4,36+28+16+14+12+10+5, 36+28+16+14+12+10+6, 36+28+16+14+12+10+7+1,36+28+16+14+12+10+7+2, 36+28+16+14+12+10+7+3, 36+28+16+14+12+10+7+4,36+28+16+14+12+10+7+5, 36+28+16+14+12+10+7+6, 36+28+16+14+12+10+8+7+1,36+28+16+14+12+10+8+7+2, 36+28+16+14+12+10+8+7+3,36+28+16+14+12+10+8+7+4, 36+28+16+14+12+10+8+7+5,36+28+16+14+12+10+8+7+6, 36+28+16+14+12+10+9+7+1,36+28+16+14+12+10+9+7+2, 36+28+16+14+12+10+9+7+3,36+28+16+14+12+10+9+7+4, 36+28+16+14+12+10+9+7+5,36+28+16+14+12+10+9+7+6, 36+28+16+14+13+10+1, 36+28+16+14+13+10+2,36+28+16+14+13+10+3, 36+28+16+14+13+10+4, 36+28+16+14+13+10+5,36+28+16+14+13+10+6, 36+28+16+14+13+10+7+1, 36+28+16+14+13+10+7+2,36+28+16+14+13+10+7+3, 36+28+16+14+13+10+7+4, 36+28+16+14+13+10+7+5,36+28+16+14+13+10+7+6, 36+28+16+14+13+10+8+7+1, 36+28+16+14+13+10+8+7+2,36+28+16+14+13+10+8+7+3, 36+28+16+14+13+10+8+7+4,36+28+16+14+13+10+8+7+5, 36+28+16+14+13+10+8+7+6,36+28+16+14+13+10+9+7+1, 36+28+16+14+13+10+9+7+2,36+28+16+14+13+10+9+7+3, 36+28+16+14+13+10+9+7+4,36+28+16+14+13+10+9+7+5, 36+28+16+14+13+10+9+7+6, 36+28+17+1,36+28+17+2, 36+28+17+3, 36+28+18+17+1, 36+28+18+17+2, 36+28+18+17+3,36+28+19+4, 36+28+19+5, 36+28+19+6, 36+28+20+1, 36+28+20+2, 36+28+20+3,36+28+21+20+1, 36+28+21+20+2, 36+28+21+20+3, 36+28+22+20+1,36+28+22+20+2, 36+28+22+20+3, 36+28+23+20+1, 36+28+23+20+2,36+28+23+20+3, 36+28+24+4, 36+28+24+5, 36+28+24+6, 36+28+25+4,36+28+25+5, 36+28+25+6, 36+28+26+4, 36+28+26+5, 36+28+26+6, 36+29+1,36+29+2, 36+29+3, 36+30, 36+31, 36+32 and 36+33.

In the list above, the numbers refer to the embodiments according totheir numbering provided hereinabove whereas “+” indicates thedependency from another embodiment. The different individualizedembodiments are separated by commas. In other words, “4+3+1” for examplerefers to embodiment 4) depending on embodiment 3), depending onembodiment 1), i.e. embodiment “4+3+1” corresponds to embodiment 1)further limited by the features of embodiments 3) and 4). Likewise,“28+18+17+1” refers to embodiment 28) depending mutatis mutandis onembodiments 17) and 18), depending on embodiment 1), i.e. embodiment“28+18+17+1” corresponds to embodiment 1) further limited by thefeatures of embodiment 28), further limited by the features ofembodiments 17) and 18).

Besides, any characteristics described in this invention for thecompounds of formula I (whether for the compounds themselves, saltsthereof, compositions containing the compounds or salts thereof, uses ofthe compounds or salts thereof, etc.) apply mutatis mutandis tocompounds of formula I_(E1), formula I_(E2), formula I_(P), formulaI_(PE1), formula I_(PE2), formula I₂, formula I₃ and formula I₃′.

The compounds of formula I can be manufactured in accordance with thepresent invention using the procedures described hereafter.

Preparation of the Compounds of Formula I General Preparation Methods:Preparation of the Compounds of Formula I:

The compounds of formula I can be manufactured by the methods givenbelow, by the methods given in the examples or by analogous methods.Optimum reaction conditions may vary with the particular reactants orsolvents used, but such conditions can be determined by a person skilledin the art by routine optimisation procedures.

Sections a) and b) hereafter describe general methods for preparingcompounds of formula I. If not indicated otherwise, the generic groupsR^(1a), R^(1b), R², R³, R⁴, A, B, Q, U and Y and the integers m and nare as defined for formula I. General synthetic methods used repeatedlythroughout the text below are referenced to and described in the abovesection entitled “General reaction techniques”. Other abbreviations usedare defined in the experimental section. In some instances the genericgroup B might be incompatible with the assembly illustrated in theprocedures and schemes below and so will require the use of protectinggroups. The use of protecting groups is well known in the art (see forexample “Protective Groups in Organic Synthesis”, T. W. Greene, P. G. M.Wuts, Wiley-Interscience, 1999).

The compounds of formula I can be obtained by methods a) or b) below:

a) By reacting the compounds of formula II

wherein A, B, Y, Q, m and n have the same meanings as in formula I, witha compound of formula III

wherein R^(1a) and R^(1b) have the same meanings as in formula I orR^(1a) represents the group COOR^(a) wherein R^(a) represent alkyl,benzyl, allyl or the group B(OAc)₂, R^(1b) represents H and X representshalogen such as Br, Cl or I in presence of an organic base such TEA orDIPEA. In the case wherein R^(a) represents alkyl, benzyl or allyl, thegroup R^(a) can be removed by treatment respectively with an inorganicbase such NaOH, hydrogenation over a noble metal catalyst such as Pd/Cor by treatment with Pd(OAc)₂ in the presence of triethyl phosphite andsodium 2-methylhexanoate. In the particular case wherein R^(a)represents B(OAc)₂ the reaction is followed by a treatment with an aq.inorganic acid such as HCl prior to purification.

b) By reacting the compounds of formula IV

wherein each of m and n represents 2, with a compound of formula V

wherein Z represents a halogen such as iodine or a sulfonate such asMsO, TsO or TfO in presence of an organic base such TEA or DIPEA usinggeneral reaction technique 1.

Preparation of the Intermediates Used in the Preparation of theCompounds of Formula I:

Compounds of formulae II and V:

The compounds of formula V can be prepared as described in or in analogyto literature procedures (WO 2008/126034 or WO 2010/041194).

The compounds of formula II can be prepared according to WO 2008/126034(m=n=1) or by one of the general routes described in Schemes 1 and 2hereafter.

In Scheme 1, Z represents iodine or a sulfonate such as OMs or OTs andPG¹ represents an amine protecting group such as Cbz or Boc.

The compounds of formula V can be reacted (Scheme 1) with the amines offormula I-1 (commercially available) in presence of a base such TEAusing general reaction technique 1 followed by removal of the amineprotecting group using general reaction technique 2. Alternatively thecompounds of formula V can be transformed into the corresponding aminesof formula I-2 using general reaction technique(s) 3 or 4 and 5 andreacted with the ketones of formula I-3 (commercially available) usinggeneral reaction technique 6 followed by removal of the amine protectinggroup using general reaction technique 2.

In Scheme 2, X^(a) represents a halogen such as chlorine or bromine, PG¹represents an amine protecting group such as Alloc or Boc and m, n, A,B, Y and Q have the same meanings as in formula I.

The compounds of formula II can be obtained by reacting the compounds offormula II-1 with the compounds of formula II-2 (described in WO2010/041194). This reaction can be performed in the presence of a NaHwhen Y═N; when Y═CH, it can be performed under conditions described forthe metal catalyzed N-arylation of 2-oxazolidinones or amides, inparticular by using CuI and 1,1,1-tris(hydroxymethyl)ethane in thepresence of Cs₂CO₃ (Chen et al., Org. Lett. (2006), 8, 5609), orPd(OAc)₂ and DPEphos in the presence of K₃PO₄.

In the particular case wherein Y═N and Q=O, the compounds of formula IIcan furthermore be prepared as described in Scheme 3 hereafter.

In Scheme 3, Xa represents a halogen such as chlorine or bromine, PG¹represents an amine protecting group such as Alloc or Boc and m, n, Aand B have the same meanings as in formula I.

The oxazolidinones of formula II-1 can be reacted (Scheme 3) with thenitropyridine derivatives of formula III-1 (prepared as described in WO2007/118130) in presence of a base such as K₂CO₃, Pd(OAc)₂ and DPEphos.The resulting oxazolidinones of formula III-2 can be treated withammonium chloride and powdered iron followed by removal of the nitrogenprotecting group using general reaction technique 2, affording thecompounds of formula II wherein Y═N and Q=O.

Compounds of formula III:

The compounds of formula III wherein R^(1a) represents carboxy andR^(1b) represents H are commercially available or can be prepared byhydrolysis of their corresponding known alkyl esters (e.g. III whereinU═N, R²=cyclopropyl and R³═H: EP 607825) in the presence of conc. aq.HCl. The compounds of formula III wherein each of R^(1a) and R^(1b)represents H can be prepared by decarboxylation under thermal conditions(between 150° C. and 250° C.) of the corresponding compounds of formulaIII wherein R^(1a) represents carboxyl. The compounds of formula IIIwherein R^(1a) and R^(1b) represent together either the group*—C(O)—NH—S—^(#) or the group *—C(OH)═N—S—^(#) wherein “*” representsthe point of attachment of R^(1a) and “^(#)” represents the point ofattachment of R^(1b) can be prepared according to or in analogy to J.Heterocycl. Chem. (1990), 27(5), 1191-1195.

Compounds of Formula IV:

The compounds of formula IV are commercially available or can beprepared as described in EP 235762, DE 2362553, DE 2840910, EP 241206 orChemical & Pharmaceutical Bulletin (1988), 36(3), 1223-8.

Compounds of Formula II-1:

The compounds of formula II-1 can be prepared as described in Scheme 4hereafter.

In Scheme 4, PG¹ represents an amine protecting group such as Alloc orBoc and m, n, A and B have the same meanings as in formula I.

The commercially available piperidine derivatives of formula IV-1 orIV-3 can be reacted (Scheme 4) with the commercially available epoxideof formula IV-2 in the presence of MgSO₄. The resulting aminoalcoholderivatives of formula IV-4 can be reacted with K₂CO₃, affording theoxazolidinone derivatives of formula II-1.

General Reaction Techniques:

General Reaction Technique 1 (Alkylation of an Amine with a Mesylate oran Iodide):

The amine derivative is reacted with the required iodide derivatives oralcohol derivatives activated as a sulfonate (OMs, ONf, ONs, OBs, OTf,OTs) in presence of an inorganic base such as K₂CO₃ or an org. base suchas TEA or DIPEA in a solvent such as THF, DMF or DMSO between 0° C. and+80° C. Further details can be found in Comprehensive OrganicTransformations. A guide to Functional Group Preparations; 2^(nd)Edition, R. C. Larock, Wiley-VC; New York, Chichester, Weinheim,Brisbane, Singapore, Toronto, (1999) Section Amines p. 779.

General Reaction Technique 2 (Removal of Amino Protecting Group):

The Cbz protecting group is removed by hydrogenolysis over a noble metalcatalyst (e.g. Pd/C or Pd(OH)₂/C). The Boc group is removed under acidicconditions such as HCl in an org. solvent such as MeOH or dioxane, orTFA neat or diluted in a solvent such DCM. The Alloc group is removed inpresence of tetrakis(triphenylphosphine) palladium(0) in presence of anallyl cation scavenger such as morpholine, dimedone or tributyltinhydride between 0° C. and 50° C. in a solvent such as THF. Furthergeneral methods to remove amine protecting groups have been described inProtecting Groups in Organic Synthesis, 3^(rd) Ed (1999), 494-653; T. W.Greene, P. G. M. Wuts; (Publisher: John Wiley and Sons, Inc., New York,N.Y.).

General Reaction Technique 3 (Formation of Azides):

The activated alcohol (activated either as a sulfonate or an iodidederivative) is reacted with sodium azide in presence of an org. basesuch as DIPEA or TEA or an inorganic base such as Na₂CO₃ in a solventsuch as DMSO or DMF between 20 and 100° C. Alternatively, the azide canalso be obtained by activation of the alcohol under Mitsunobu conditionsin presence of PPh₃ and DEAD or DIAD in a solvent such as THF, DMF, DCMor DME between −20 and +60° C. as reviewed in Synthesis (1981), 1-28.Alternatively, the alcohol is directly reacted with DPPA in presence ofa base such as TEA or DBU in a solvent such as THF between −20 and +60°C. as described in J. Org. Chem. (1993), 58, 5886-5888.

General Reaction Technique 4 (Formation of Phthalimides):

The activated alcohol (activated either as a sulfonate or an iodidederivative) is reacted with potassium phthalimide in a solvent such asDMSO or DMF between 20 and 100° C.

General Reaction Technique 5 (Formation of Amines):

The azides are hydrogenated over a noble metal catalyst such as Pd/C ina solvent such as MeOH or EA. In case the molecule is containing anunsaturated double or triple bond, the reduction can be performed usingPPh₃ in the presence of water as described in J. Med. Chem. (1993), 36,2558-68. Besides, the phthalimide derivatives are treated between 50 and120° C. with a hydrazine derivative such as hydrazine hydrate,methylhydrazine or an amine such as N¹,N¹-dimethylpropane-1,3-diamine ina solvent such as MeOH or EtOH. Further general methods have beendescribed in Protecting Groups in Organic Synthesis, 3^(rd) Ed (1999),564-566; T. W. Greene, P. G. M. Wuts (Publisher: John Wiley and Sons,Inc., New York).

General Reaction Technique 6 (Reductive Amination);

The reaction between the amine and the aldehyde or ketone is performedin a solvent system allowing the removal of the formed water throughphysical or chemical means (e.g. distillation of the solvent-waterazeotrope or presence of drying agents such as molecular sieves, MgSO₄or Na₂SO₄). Such solvent is typically toluene, Hex, THF, DCM or DCE or amixture of solvents such as DCE/MeOH. The reaction can be catalyzed bytraces of acid (usually AcOH). The intermediate imine is reduced with asuitable reducing agent (e.g. NaBH₄, NaBH₃CN, or NaBH(OAc)₃ or throughhydrogenation over a noble metal catalyst such as Pd/C. The reaction iscarried out between −10° C. and 110° C., preferably between 0° C. and60° C. The reaction can also be carried out in one pot. It can also beperformed in protic solvents such as MeOH or water in presence of apicoline-borane complex (Tetrahedron (2004), 60, 7899-7906).

Particular embodiments of the invention are described in the followingExamples, which serve to illustrate the invention in more detail withoutlimiting its scope in any way.

EXAMPLES Abbreviations As Used Herein and in the Description Above

Ac acetyl

Alloc allyloxycarbonyl

aq. aqueous

Boc tert-butoxycarbonyl

Bs 4-bromobenzenesulfonyl (brosylate)

Bu butyl

Cbz benzyloxycarbonyl

CC column chromatography over silica gel

Cipro ciprofloxacin

DAD diode array detection

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DCE 1,2-dichloroethane

DCM dichloromethane

DEAD diethyl azodicarboxylate

dil. diluted

DPEphos bis(2-diphenylphosphinophenyl)ether

DIAD diisopropyl azodicarboxylate

DIPEA N,N-diisopropylethylamine

DME 1,2-dimethoxyethane

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

DPPA diphenyl phosphoryl azide

EA ethyl acetate

ELSD evaporative light scattering detector

ESI electron spray ionisation

eq. equivalent

Et ethyl

Hept heptane

Hex hexane

HPLC high pressure liquid chromatography

LC liquid chromatography

Me methyl

MS mass spectroscopy

Ms methanesulfonyl (mesyl)

Nf nonafluorobutanesulfonyl

Ns 4-nitrobenzenesulfonyl (nosylate)

org. organic

Pd/C palladium on carbon

Pd(OH)₂/C palladium dihydroxide on carbon

Ph phenyl

PPh₃ triphenylphosphine

Pyr pyridine

rac racemic

rt room temperature

sat. saturated

TBME tert-butylmethylether

tBu tert-butyl

TEA triethylamine

Tf trifluoromethanesulfonyl (triflyl)

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

Ts para-toluenesulfonyl

wt % percent in weight

All temperatures are stated in ° C. All temperatures are stated in ° C.Unless otherwise indicated, the reactions take place at rt.

Analytical TLC characterisations were performed with 0.2 mm plates:Merck, Silica gel 60 F₂₅₄. Elution is performed with EA, Hept, DCM, MeOHor mixtures thereof. Detection was done with UV or with a solution ofKMnO₄ (3 g), K₂CO₃ (20 g), 5% NaOH (3 mL) and H₂O (300 mL) withsubsequent heating.

CCs are performed using Brunschwig 60A silica gel (0.032-0.63 mm);elution is performed with EA, Hept, DCM, MeOH or mixtures thereof. Inthe cases of compounds containing an acid function, 1% of AcOH is addedto the eluent(s).

Compounds are characterized by ¹H-NMR (300 MHz) (Varian Oxford); or by¹H-NMR (400 MHz) (Bruker Advance 400). Chemical shifts δ are given inppm relative to the solvent used; multiplicities: s=singlet, d=doublet,t=triplet, q=quadruplet, p=pentuplet, hex=hexet, hep=heptet,m=multiplet, br.=broad, coupling constants are given in Hz.Alternatively compounds are characterized by LC-MS (Sciex API 2000 withAgilent 1100 Binary Pump with DAD and ELSD or an Agilent quadrupole MS6140 with Agilent 1200 Binary Pump, DAD and ELSD); by TLC (TLC platesfrom Merck, Silica gel 60 F₂₅₄); or by melting point. Compounds arepurified by chromatography on Silica gel 60A. NH₄OH as used for CC is25% aq.

The LC-MS data have been performed using the following three respectivemethods:

Method 1 (MS1):

-   -   Pump: Waters Acquity Binary, Solvent Manager; MS: Waters SQ        Detector; DAD: Acquity UPLC PDA Detector; ELSD: Acquity UPLC        ELSD.    -   Column: Acquity UPLC CSH C18 1.7 μm, 2.1×50 mm from Waters,        thermostated in the Acquity UPLC Column Manager at 60° C.    -   Eluents: A: H₂O+0.05% formic acid; B: MeCN+0.045% formic acid.        Gradient: 2% B→98% B over 3.0 min. Flow: 0.6 mL/min.    -   Detection: UV 214 nm, ELSD and MS; the retention time _(tR) is        given in min.

Method 2 (MS2):

-   -   Thermo MSQ Plus with Dionex GHP 3200 Binary Pump, DAD and ELSD.    -   Eluents: A: H₂O+0.04% TFA; B: MeCN; Gradient: 2% B→98% B over        3.0 min. Flow: 0.6 mL/min    -   Column: ZorbaxSB-Aq, 3.7 μm, 4.6×50 mm/USXA001358

Method 3 (MS3):

-   -   Same method as MS2 but    -   Column: Waters Atlantis T3, 5 μm, 4.6×30 mm/01273031412503.

The number of decimals given for the corresponding [M+H+] peak(s) ofeach tested compound depends upon the accuracy of the LC-MS deviceactually used.

The HPLCs are done over a stationary phase such as a rapid resolutionZorbax SB C18 (1.8 μm) column, or a rapid resolution Zorbax Eclipse PlusC18 (1.8 μm) column. Typical HPLC conditions are a gradient of eluent A(water:MeCN 95:5 with 0.1% of formic acid, in the presence or absence of5 mmol/L ammonium formate) and eluent B (MeCN:water 95:5 with 0.1% offormic acid, in the presence or not of 5 mmol/L ammonium formate), at aflow rate of 0.8 to 5 mL/min.

Example 11-cyclopropyl-6-fluoro-4-oxo-7-{4-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]-piperazin-1-yl}-1,4-dihydro-quinoline-3-carboxylicacid

A mixture of1-cyclopropyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (commercial; 331 mg),6-((S)-5-iodomethyl-2-oxooxazolidin-3-yl)-4H-benzo[1,4]thiazin-3-one(prepared according to WO 2008/126034; 395 mg) and DIPEA (0.5 ml) inDMSO (6 ml) was heated at 80° C. for 24 h. The reaction mixture wasallowed to reach rt, poured on 0.1N HCl (50 ml) and filtered. Theresulting solid was purified by CC (DCM/MeOH 19:1 to 9:1 to 4:1,followed by DCM/MeOH 19:1+1% AcOH), affording after concentration underreduced pressure and subsequent stirring in MeOH/EA a beige solid.

¹H NMR (DMSO-d₆) δ: 11.40 (s, 1H); 10.55 (s, 1H); 8.68 (s, 1H);7.95-7.80 (m, 1H); 7.59-7.45 (m, 1H); 7.36-7.25 (m, 2H); 7.15-7.06 (m,1H); 4.99-4.79 (m, 1H); 4.18-4.01 (m, 1H); 3.81-3.62 (m, 2H); 3.41 (s,2H); 3.34-3.18 (m, 4H); 2.83-2.62 (m, 6H); 1.37-1.21 (m, 2H); 1.13-0.97(m, 2H). MS (ESI, m/z): 594.4 [M+H⁺] for C₂₉H₂₈N₅O₆FS; t_(R)=0.65 min(MS2).

Example 21-cyclopropyl-6-fluoro-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid

A mixture of7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid (commercial; 141 mg),6-[(5R)-5-[(3-azetidinylamino)methyl]-2-oxo-3-oxazolidinyl]-2H-1,4-benzothiazin-3(4H)-one(prepared according to WO 2008/126034; 167 mg) and TEA (0.15 ml) in MeCN(4 ml) was heated at 75° C. for 2 h. The reaction mixture was allowed toreach rt, diluted with water, filtered and the solid was washed withMeOH and EA, affording a beige solid.

¹H NMR (DMSO-d₆) δ: 10.54 (s, 1H); 8.54 (s, 1H); 7.94 (d, J=11.5 Hz,1H); 7.32-7.26 (m, 2H); 7.11 (dd, J=2.3 Hz, J=8.6 Hz, 1H); 4.79-4.62 (m,1H); 4.59-4.36 (m, 2H); 4.17-3.92 (m, 3H); 3.89-3.70 (m, 2H); 3.70-3.56(m, 1H); 3.41 (s, 2H); 2.95-2.75 (m, 3H); 1.21-0.98 (m, 4H). MS (ESI,m/z): 582.2 [M+H⁺] for C₂H₂₅N₆O₆FS; t_(R)=0.64 min (MS2).

Example 31-cyclopropyl-6-fluoro-4-oxo-7-{4-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]-piperazin-1-yl}-1,4-dihydro-quinoline-3-carboxylicacid

In analogy to Example 1, starting from1-cyclopropyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (commercial; 166 mg) and6-[(5R)-5-[[(methylsulfonyl)oxy]methyl]-2-oxo-3-oxazolidinyl]-2H-pyrido[3,2-b]-1,4-thiazin-3(4H)-one(prepared in analogy to its (S) enantiomer described in WO 2010/041194;180 mg), the title compound was obtained as a beige solid after CC(DCM/MeOH 9:1) and crystallization from EtOH.

¹H NMR (DMSO-d₆) δ: 11.40 (s, 1H), 10.84 (s, 1H); 8.65 (s, 1H); 7.89 (d,J=13.3 Hz, 1H); 7.81-7.74 (m, 1H); 7.70-7.64 (m, 1H), 7.55 (d, J=7.4 Hz,1H); 4.97-4.81 (m, 1H); 4.26-4.13 (m, 1H); 3.89-3.74 (m, 2H); 3.51 (s,2H); 3.36-3.22 (m, 4H); 2.82-2.65 (m, 6H); 1.37-1.22 (m, 2H); 1.22-1.11(m, 2H). MS (ESI, m/z): 595.18 [M+H⁺] for C₂₈H₂₇N₆O₆FS; t_(R)=1.13 min(MS 1).

Example 41-cyclopropyl-6-fluoro-4-oxo-7-{4-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]-piperazin-1-yl}-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid 4.1.4-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]-piperazine-1-carboxylicacid tert-butyl ester

A solution of6-((S)-5-iodomethyl-2-oxooxazolidin-3-yl)-4H-benzo[1,4]thiazin-3-one(prepared according to WO 2008/126034; 1.0 g) and Boc-piperazine (1.43g) in DMF (10 ml) was stirred overnight at rt and 2 h at 60° C. Thereaction mixture was allowed to reach rt, diluted with water andextracted with EA (2×). The combined org. layers were washed with waterand brine, dried over MgSO₄, filtered and evaporated under reducedpressure, affording after stirring the residue in TBME a colourlesssolid.

¹H NMR (CDCl₃) δ: 8.15 (s, 1H); 7.41 (d, J=2.3 Hz, 1H); 7.29 (d, J=8.5Hz, 1H); 6.95 (dd, J=2.3 Hz, J=8.6 Hz, 1H); 4.88-4.67 (m, 1H); 4.05 (t,J=8.7 Hz, 1H); 3.79 (dd, J=7.0 Hz, J=8.8 Hz, 1H); 3.47-3.36 (m, 4H);3.41 (s, 2H); 2.80-2.67 (m, 2H); 2.64-2.43 (m, 4H); 1.46 (s, 9H). MS(ESI, m/z): 449.1 [M+H⁺].

4.2.6-((R)-2-oxo-5-piperazin-1-ylmethyl-oxazolidin-3-yl)-4H-benzo[1,4]thiazin-3-one

A solution of intermediate 4.1 (730 mg) in DCM (10 ml) was treated withtriethylsilane (0.28 ml) and TFA (3.12 ml). After stirring at rt for 30min the solution was evaporated under reduced pressure and the residuewas taken up in DCM and washed with a dil. NH₄OH solution. The aq. layerwas extracted with DCM/MeOH (9:1) and the combined org. layers weredried over MgSO₄, filtered and evaporated under reduced pressure,affording a colourless foam.

¹H NMR (DMSO-d₆) δ: 10.52 (s, 1H); 7.35-7.24 (m, 2H); 7.11 (dd, J=2.2Hz, J=8.6 Hz, 1H); 4.88-4.72 (m, 1H); 4.05 (t, J=8.8 Hz, 1H); 3.68 (dd,J=7.1 Hz, J=8.5 Hz, 1H); 3.42 (s, 2H); 2.72-2.61 (m, 4H); 2.61-2.56 (m,2H); 2.43-2.31 (m, 4H). MS (ESI, m/z): 349.0 [M+H⁺] for C₁₆H₂₀N₄O₃S.

4.3.1-cyclopropyl-6-fluoro-4-oxo-7-{4-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]-piperazin-1-yl}-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid

In analogy to Example 2, starting from intermediate 4.2 (174 mg) and7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid (commercial; 141 mg), the title compound was obtained as acolourless foam.

¹H NMR (DMSO-d₆) δ: 11.40 (s, 1H), 10.54 (s, 1H); 8.60 (s, 1H); 8.06 (d,J=13.5 Hz, 1H); 7.33 (d, J=2.2 Hz, 1H); 7.30 (d, J=8.6 Hz, 1H); 7.11(dd, J=2.3 Hz, J=8.7 Hz, 1H); 4.95-4.78 (m, 1H); 4.14-4.02 (m, 1H);3.92-3.80 (m, 4H); 3.78-3.62 (m, 2H); 3.42 (s, 2H); 2.79-2.60 (m, 6H);1.25-1.11 (m, 2H); 1.11-1.02 (m, 2H). MS (ESI, m/z): 595.18 [M+H⁺] forC₂₈H₂₇N₆O₆FS t_(R)=1.12 min (MS1).

Example 56-((R)-5-{[1-(8-cyclopropyl-3-fluoro-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-yl)-azetidin-3-ylamino]-methyl}-2-oxo-oxazolidin-3-yl)-4H-benzo[1,4]thiazin-3-one5.1. 7-chloro-1-cyclopropyl-6-fluoro-1H-[1,8]naphthyridin-4-one

7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid (2.0 g) was added portionwise to a boiling solution of Dowtherm (50ml heated at 250° C.) and further stirred at this temperature for 1 h.The reaction mixture was allowed to reach rt and diluted with 1N NaOH(100 ml) and extracted with EA. The org. phase was discarded. The aq.phase was acidified with 3N HCl and extracted with ether/EA. The aq.layer was filtered and the filtrate was extracted with ether/EA. Thecombined org. layers were washed with water and brine dried over MgSO₄,filtered and evaporated under reduced pressure affording a solid whichwas stirred in Hept/EA and filtered. The filtrate was concentrated underreduced pressure and purified by CC (EA to EA/MeOH 9:1), affording abeige solid.

¹H NMR (CDCl₃) δ: 8.36 (d, J=7.5 Hz, 1H); 7.73 (d, J=8.0 Hz, 1H); 6.25(d, J=8.0 Hz, 1H); 3.62-3.51 (m, 1H); 1.33-1.20 (m, 2H); 1.03-0.93 (m,2H).

MS (ESI, m/z): 239.16 [M+H⁺] for C₁₁H₈N₂OClF; t_(R)=0.67 min (MS3).

5.2.6-((R)-5-{[1-(8-cyclopropyl-3-fluoro-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-yl)-azetidin-3-ylamino]-methyl}-2-oxo-oxazolidin-3-yl)-4H-benzo[1,4]thiazin-3-one

In analogy to Example 2, starting from intermediate 5.1 (30 mg) and6-[(5R)-5-[(3-azetidinylamino)methyl]-2-oxo-3-oxazolidinyl]-2H-1,4-benzothiazin-3(4H)-one(prepared according to WO 2008/126034; 42 mg), the title compound wasobtained as a beige solid.

¹H NMR (DMSO-d₆) δ: 10.54 (s, 1H); 7.77 (d, J=3.9 Hz, 1H); 7.74 (d,J=7.8 Hz, 1H); 7.36-7.25 (m, 3H); 7.14-7.07 (m, 1H); 4.76-4.63 (m, 1H);4.44-4.30 (m, 1H); 4.09-3.89 (m, 3H); 3.85-3.69 (m, 2H); 3.47-3.42 (m,1H); 3.41 (s, 2H); 2.90-2.76 (m, 4H); 1.07-0.85 (m, 4H). MS (ESI, m/z):537.17 [M+H⁺] for C₂₆H₂₅N₆O₄FS; t_(R)=0.95 min (MS1).

Example 61-cyclopropyl-6-fluoro-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid

In analogy to Example 2, starting from7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid (70 mg) and6-[(5R)-5-[(3-azetidinylamino)methyl]-2-oxo-3-oxazolidinyl]-2H-1,4-benzoxazin-3(4H)-one(prepared according to WO 2008/126034; 89 mg), the title compound wasobtained as a beige solid.

¹H NMR (DMSO-d₆) δ: 11.40 (s, 1H); 11.16 (s, 1H); 8.54 (s, 1H); 7.94 (d,J=11.5 Hz, 1H); 7.59 (d, J=8.7 Hz, 1H); 7.40 (d, J=8.7 Hz, 1H);4.78-4.62 (m, 1H); 4.59 (s, 2H); 4.54-4.38 (m, 2H); 4.21-3.95 (m, 3H);3.91-3.74 (m, 2H); 3.71-3.56 (m, 1H); 2.91-2.81 (m, 2H); 1.21-0.99 (m,4H). MS (ESI, m/z): 566.18 [M+H⁺] for C₂₆H₂₄N₇O₇F; t_(R)=1.00 min (MS1).

Example 71-cyclopropyl-8-methoxy-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-quinoline-3-carboxylicacid

The title compound was prepared in analogy to Example 2, starting from1-cyclopropyl-7-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid anhydride with boric acid (1:1) and with acetic acid (1:2) (101 mg;prepared according to WO 2010/056633) and 6-[(5R)-5-[(3-azetidinylamino)-methyl]-2-oxo-3-oxazolidinyl]-2H-1,4-benzothiazin-3(4H)-one(prepared according to WO 2008/126034; 167 mg). At the end of thereaction, the reaction mixture was concentrated under reduced pressureand the residue was taken up in MeOH and treated with 1N HCl in MeOH (3ml) for 15 min. The reaction mixture was diluted with water (2 ml) andthe solid was filtered off. The org. phase was concentrated underreduced pressure and purified by CC (DCM/MeOH 9:1 followed by DCM/MeOH9:1+1% AcOH), affording after evaporation and stirring of the residuewith MeOH/TBME a beige solid.

¹H NMR (DMSO-d₆) δ: 11.40 (s, 1H), 10.56 (s, 1H); 8.59 (s, 1H);7.99-7.83 (m, 1H); 7.33 (d, J=2.3 Hz, 1H); 7.29 (d, J=8.6 Hz, 1H); 7.10(dd, J=2.3 Hz, J=8.6 Hz, 1H); 6.84-6.68 (m, 1H); 4.78-4.61 (m, 1H);4.33-4.18 (m, 2H); 4.11-3.98 (m, 2H); 3.83-3.67 (m, 4H); 3.55 (s, 3H);3.41 (s, 2H); 2.85 (d, J=5.2 Hz, 2H); 1.80 (br. s, 1H); 1.13-0.99 (m,2H); 0.99-0.86 (m, 2H). MS (ESI, m/z): 592.19 [M+H⁺] for C₂₉H₂₉N₅O₇S;t_(R)=1.01 min (MS1).

Example 81-cyclopropyl-8-methoxy-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-quinoline-3-carboxylicacid

In analogy to Example 2, starting from1-cyclopropyl-7-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid anhydride with boric acid (1:1) and with acetic acid (1:2) (101 mg;prepared according to WO 2010/056633) and6-[(5R)-5-[(3-azetidinylamino)methyl]-2-oxo-3-oxazolidinyl]-2H-1,4-benzoxazin-3(4H)-one(prepared according to WO 2008/126034; 89 mg), the title compound wasobtained as a beige solid.

¹H NMR (DMSO-d₆) δ: 11.40 (s, 1H), 11.16 (s, 1H); 8.61 (s, 1H);7.98-7.86 (m, 1H); 7.62-7.55 (m, 1H); 7.41 (d, J=8.7 Hz, 1H); 6.86-6.69(m, 1H); 4.78-4.63 (m, 1H); 4.59 (s, 2H); 4.34-4.18 (m, 2H); 4.18-4.03(m, 2H); 3.91-3.80 (m, 1H); 3.80-3.65 (m, 3H); 3.55 (s, 3H); 2.85 (d,J=4.9 Hz, 2H); 1.86 (s, 1H); 1.15-1.01 (m, 2H); 1.01-0.90 (m, 2H). MS(ESI, m/z): 577.21 [M+H⁺] for C₂₈H₂₈N₆O₈; t_(R)=0.94 min (MS1).

Example 91-ethyl-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid

In analogy to Example 2, starting from7-chloro-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid(prepared according to U.S. Pat. No. 3,149,104; 63 mg) and6-[(5R)-5-[(3-azetidinylamino)methyl]-2-oxo-3-oxazolidinyl]-2H-1,4-benzoxazin-3(4H)-one(prepared according to WO 2008/126034; 89 mg), the title compound wasobtained as a beige solid.

¹H NMR (DMSO-d₆) δ: 11.40 (s, 1H); 11.22 (s, 1H); 8.93 (s, 1H), 8.31 (d,J=8.9 Hz, 1H); 7.62-7.56 (m, 1H); 7.46-7.39 (m, 1H); 6.75 (d, J=8.9 Hz,1H); 4.60 (s, 2H); 4.53-4.36 (m, 4H); 4.32-4.15 (m, 4H); 3.83 (dd, J=6.9Hz, J=10.5 Hz, 1H); 3.48-3.24 (m, 4H); 1.38 (t, J=7.0 Hz, 3H). MS (ESI,m/z): 536.19 [M+H⁺] for C₂₅H₂₅N₇O₇; t_(R)=0.92 min (MS1).

Example 101-cyclopropyl-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid 10.1.7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid

A suspension of7-chloro-1-cyclopropyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid ethyl ester (prepared according to EP 607825; 500 mg) in 6N HCl (6ml) was stirred at 100° C. for 30 min. The reaction mixture was allowedto reach rt and the resulting crystals were collected by filtration andsequentially washed with water and MeOH, affording a beige solid.

¹H NMR (DMSO-d₆) δ: 11.40 (s, 1H), 8.81 (s, 1H); 8.70 (d, J=8.4 Hz, 1H);7.78 (d, J=8.4 Hz, 1H); 3.85-3.74 (m, 1H); 1.27-1.07 (m, 4H). MS (ESI,m/z): 265.1 [M+H⁺] for C₁₂H₉N₂O₃Cl; t_(R)=0.7 min (MS3).

10.2.1-cyclopropyl-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid

In analogy to Example 2, starting from intermediate 10.1 (66 mg) and6-[(5R)-5-[(3-azetidinylamino)methyl]-2-oxo-3-oxazolidinyl]-2H-1,4-benzothiazin-3(4H)-one(prepared according to WO 2008/126034; 84 mg), the title compound wasobtained as a beige solid.

¹H NMR (DMSO-d₆) δ: 11.40 (s, 1H), 10.54 (s, 1H); 8.53 (s, 1H); 8.22 (d,J=8.9 Hz, 1H); 7.33 (d, J=2.3 Hz, 1H); 7.32-7.26 (m, 1H); 7.10 (dd,J=2.3 Hz, J=8.5 Hz, 1H); 6.65 (d, J=8.9 Hz, 1H); 4.77-4.63 (m, 1H);4.37-4.27 (m, 2H); 4.05 (t, J=8.7 Hz, 1H); 3.93-3.72 (m, 4H); 3.70-3.58(m, 1H); 3.42 (s, 2H); 2.91-2.80 (m, 2H); 1.18-0.93 (m, 4H).

MS (ESI, m/z): 563.17 [M+H⁺] for C₂₇H₂₆N₆O₆S; t_(R)=1.01 min (MS1).

Example 111-methyl-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid

In analogy to Example 2, starting from7-chloro-1,4-dihydro-1-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid(60 mg; prepared according to JP 01165584) and6-[(5R)-5-[(3-azetidinylamino)methyl]-2-oxo-3-oxazolidinyl]-2H-1,4-benzoxazin-3(4H)-one(prepared according to WO 2008/126034; 89 mg), the title compound wasobtained as a beige solid.

¹H NMR (DMSO-d₆) δ: 11.40 (s, 1H), 11.23 (s, 1H); 8.92 (s, 1H); 8.32 (d,J=8.9 Hz, 1H); 7.62-7.56 (m, 1H); 7.44 (d, J=8.8 Hz, 1H); 6.76 (d, J=8.9Hz, 1H); 5.09-5.97 (m, 1H); 4.61 (s, 2H); 4.52-4.39 (m, 1H); 4.38-4.21(m, 4H); 3.91 (s, 3H); 3.88-3.78 (m, 1H); 3.55-3.33 (m, 4H). MS (ESI,m/z): 522.16 [M+H⁺] for C₂₄H₂₃N₇O₇; t_(R)=0.47 min (MS3).

Example 126-fluoro-1-methyl-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid

In analogy to Example 2, starting from7-chloro-6-fluoro-1,4-dihydro-1-methyl-4-oxo-1,8-naphthyridine-3-carboxylicacid (64 mg; prepared according to WO 2011/037433) and6-[(5R)-5-[(3-azetidinylamino)methyl]-2-oxo-3-oxazolidinyl]-2H-1,4-benzoxazin-3(4H)-one(prepared according to WO 2008/126034; 89 mg), the title compound wasobtained as a beige solid.

¹H NMR (DMSO-d₆) δ: 11.40 (s, 1H), 11.16 (s, 1H); 8.87 (s, 1H); 7.93 (d,J=11.5 Hz, 1H); 7.62-7.55 (m, 1H); 7.40 (d, J=8.7 Hz, 1H); 4.78-4.61 (m,1H); 4.58 (s, 2H); 4.55-4.34 (m, 2H); 4.19-3.92 (m, 3H); 3.87 (s, 3H);3.86-3.74 (m, 2H), 2.93-2.77 (m, 2H).

MS (ESI, m/z): 540.16 [M+H⁺] for C₂₄H₂₂N₇O₇F; t_(R)=0.91 min (MS1).

Example 131-benzyl-6-fluoro-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid

In analogy to Example 2, starting from1-benzyl-7-chloro-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid (83 mg; commercially available or prepared by hydrolysis of thecorresponding ester obtained according to CN 101792443 in the presenceof 6M HCl) and6-[(5R)-5-[(3-azetidinylamino)methyl]-2-oxo-3-oxazolidinyl]-2H-1,4-benzoxazin-3(4H)-one(prepared according to WO 2008/126034; 89 mg), the title compound wasobtained as a beige solid.

¹H NMR (DMSO-d₆) δ: 11.40 (s, 1H), 11.16 (s, 1H); 8.87 (s, 1H);7.93=11.5 Hz, 1H); 7.63-7.56 (m, 1H); 7.40 (d, J=8.7 Hz, 1H); 7.41-7.20(m, 5H); 5.62 (s, 2H); 4.78-4.61 (m, 1H); 4.59 (s, 2H); 4.55-4.31 (m,2H); 4.20-4.08 (m, 1H); 4.07-3.91 (m, 2H); 3.90-3.70 (m, 2H); 2.91-2.76(m, 2H). MS (ESI, m/z): 616.20 [M+H⁺] for C₃₀H₂₆N₇O₇F; t_(R)=1.19 min(MS1).

Example 141-cyclopropyl-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid

In analogy to Example 2, starting from intermediate 10.1 (66 mg) and6-[(5R)-5-[(3-azetidinylamino)methyl]-2-oxo-3-oxazolidinyl]-2H-1,4-benzoxazin-3(4H)-one(prepared according to WO 2008/126034; 89 mg), the title compound wasobtained as a beige solid.

¹H NMR (DMSO-d₆) δ: 11.40 (s, 1H), 11.15 (s, 1H); 8.53 (s, 1H); 8.21 (d,J=8.9 Hz, 1H); 7.62-7.55 (m, 1H); 7.40 (d, J=8.7 Hz, 1H); 6.64 (d, J=8.9Hz, 1H); 4.78-4.62 (m, 1H); 4.59 (s, 2H); 4.37-4.25 (m, 2H); 4.20-4.07(m, 1H); 3.93-3.72 (m, 4H); 3.71-3.58 (m, 1H); 2.91-2.81 (m, 2H);1.21-1.08 (m, 2H); 1.08-0.97 (m, 2H).

MS (ESI, m/z): 548.19 [M+H⁺] for C₂₆H₂₅N₇O₇F; t_(R)=0.93 min (MS1).

Example 156-fluoro-1-(2-hydroxy-ethyl)-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid 15.1. (Z)-Ethyl2-(2,6-dichloro-5-fluoronicotinoyl)-3-((2-hydroxyethyl)amino)acrylate

A solution of2,6-dichloro-α-(ethoxymethylene)-5-fluoro-β-oxo-3-pyridinepropanoic acidethyl ester (1.00 g; prepared according to EP 132845) was treated withethanolamine (0.18 mL). After a few minutes, the reaction mixture becamesticky and was diluted with Hept/ether (1:1; 10 mL). After furtherstirring at rt for 1.5 h, the solvents were evaporated under reducedpressure and the crude yellow oil was directly used in the next step.

¹H NMR (DMSO-d₆) δ: 8.22 (s, 1H); 8.02 (d, J=7.9 Hz, 1H); 3.90 (q, J=7.1Hz, 2H); 3.61-3.45 (m, 4H); 3.34 (t, J=5.7 Hz, 1H); 0.94 (t, J=7.1 Hz,3H). MS (ESI, m/z): 350.94 [M+H⁺] (MS3).

15.2. Ethyl7-chloro-6-fluoro-1-(2-hydroxyethyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

A solution of intermediate 15.1 (1.04 g) in THF (15 mL) was treated at0° C. with LiHMDS (3.11 ml). The reaction mixture was further stirred atrt for 1 h, filtered and the solid was washed with THF. The resultingsolid was purified by CC (DCM/MeOH 9:1 to 4:1), affording a yellowsolid.

¹H NMR (DMSO-d₆) δ: 8.73 (s, 1H); 8.45 (d, J=7.9 Hz, 1H); 4.98-4.90 (m,1H); 4.44 (t, J=5.1 Hz, 2H); 4.23 (q, J=7.1 Hz, 2H); 3.78-3.67 (m, 2H);1.27 (t, J=7.1 Hz, 3H).

MS (ESI, m/z): 314.94 [M+H⁺] (MS3).

15.3.7-chloro-6-fluoro-1-(2-hydroxy-ethyl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid

A suspension of intermediate 15.2 (330 mg) in 6M HCl (40 ml) was stirredat 100° C. for 1 h. The reaction mixture was allowed to reach rt and theresulting solid was collected by filtration, affording a beige solid.

¹H NMR (DMSO-d₆) δ: 11.40 (s, 1H); 9.05 (s, 1H); 8.70 (d, J=7.7 Hz, 1H);4.66-4.55 (m, 2H); 3.76 (t, J=5.2 Hz, 2H). MS (ESI, m/z): 286.91 [M+H⁺](MS3).

15.4.6-fluoro-1-(2-hydroxy-ethyl)-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid

In analogy to Example 2, starting from intermediate 15.3 (72 mg) and6-[(5R)-5-[(3-azetidinylamino)methyl]-2-oxo-3-oxazodinyl]-2H-1,4-benzoxazin-3(4H)-one(prepared according to WO 2008/126034; 89 mg), the title compound wasobtained as a beige solid.

¹H NMR (DMSO-d₆) δ: 11.40 (s, 1H), 11.15 (s, 1H); 8.72 (s, 1H); 7.96 (d,J=11.6 Hz, 1H); 7.63-7.53 (m, 1H); 7.40 (d, J=8.7 Hz, 1H); 4.97-4.83 (m,1H); 4.78-4.61 (m, 1H); 4.59 (s, 2H); 4.54-4.29 (m, 4H); 4.20-3.90 (m,3H); 3.89-3.65 (m, 4H); 2.93-2.73 (m, 2H).

MS (ESI, m/z): 570.18 [M+H⁺] for C₂₅H₂₄N₇O₈F; t_(R)=0.87 min (MS1).

Example 161-cyclopropyl-6-fluoro-4-oxo-7-{4-[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]-piperazin-1-yl}-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid

The title compound was obtained as a beige solid in analogy to Example 4but using6-((R)-5-iodomethyl-2-oxooxazolidin-3-yl)-4H-benzo[1,4]thiazin-3-one(prepared according to WO 2008/126034) in the first step. Compared toExample 4, for the intermediate and the final compound the yields ofpreparation were in the same range and identical spectroscopic data (MS,NMR) were collected.

Example 171-cyclopropyl-6-fluoro-4-oxo-7-(4-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-piperidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid 17.1.(4-((R)-3-benzyloxycarbonylamino-2-hydroxy-propylamino)-piperidine-1-carboxylicacid tert-butyl ester

A solution of [(2S)-oxiranylmethyl]-carbamic acid benzyl ester (15.6 g;prepared according to WO 2004/002973) and 4-(N-Boc-amino)piperidine(15.1 g) in MeOH (100 mL) was treated with MgSO₄ (12.3 g) and the whitesuspension was stirred at rt for 6 h. The mixture was evaporated,suspended in DCM and partionated between water (1 l) and DCM (1 l). Thelayers were separated and the aq. layer was reextracted with DCM. Thecombined org. layers were evaporated and purified by CC (EE to EE/MeOH9:1), affording a yellow oil.

MS (ESI, m/z): 408.12 [M+H⁺] for C₂₁H₃₃N₃O₅; t_(R)=0.66 min (MS2).

17.2.4-[((R)-2-oxo-oxazolidin-S-ylmethyl)-amino]-piperidine-1-carboxylic acidtert-butyl ester

A solution of intermediate 17.1 (3.2 g) in MeOH (36 ml) was treated withK₂CO₃ (1.24 g) and stirred at 60° C. for 3.5 h. The reaction mixture wasconcentrated in vacuo and the residue was taken up in EA/water. The aq.layer was extracted 2× with EA. The combined org. layers were washedwith brine, dried over MgSO₄, filtered, evaporated and purified by CC(EA/MeOH 9:1), affording a yellow oil.

MS (ESI, m/z): 300.06 [M+H⁺] for C₁₄H₂₅N₃O₄; t_(R)=0.49 min (MS2).

17.3.4-{[(R)-3-(5-ethoxycarbonylmethoxy-6-nitro-pyridin-2-yl)-2-oxo-oxazolidin-5-ylmethyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester

A 50 ml flask was charged with ethyl(6-bromo-2-nitropyridin-3-yloxy)acetate (1.1 g; prepared as described inWO 2007/118130), intermediate 17.2 (1.2 g) and diluted in dioxane (18ml). Pd(OAc)₂ (41.2 mg), DPEphos (198 mg) and powdered K₂CO₃ (621 mg)were added and the suspension was degassed with argon. The mixture washeated in a sealed flask at 85° C. for 2 h. The reaction mixture wascooled to rt and partitioned between EA and water. The org. layer waswashed with brine, dried over MgSO₄, concentrated under reduced pressureand purified by CC (EA to EA/MeOH 9:1), affording an off-white foam.

MS (ESI, m/z): 524.14 [M+H⁺] for C₂₃H₃₃N₅O₉; t_(R)=0.72 min (MS2).

17.4.4-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester

Iron powder (720 mg) was added to a solution of ammonium chloride (1.15g) in H₂O/MeOH (1:1; 18 ml). The suspension was heated to 40° C. andtreated dropwise with a solution of intermediate 17.3 (1.5 g) in MeOH(28.7 ml). The reaction was further stirred at 70° C. for 5 h. Thereaction mixture was filtered over a pad of Celite and washed with MeOH.The filtrate was acidified with AcOH (9 ml) and the yellow solution wasstirred overnight at 85° C. The solvent was concentrated under reducedpressure and the suspension was triturated with H₂O, cooled to 0° C. andfiltrated. The filter cake was then washed with water and ether,affording an off-white solid.

MS (ESI, m/z): 448.04 [M+H⁺] for C₂₁H₂₉N₅O₆; t_(R)=0.61 min (MS2).

17.5.6-[(R)-2-oxo-5-(piperidin-4-ylaminomethyl)-oxazolidin-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-onehydrochloride

A suspension of intermediate 17.4 (900 mg) in dioxane/MeOH (1:1; 20 ml)was treated at rt with 4M HCl in dioxane (5.2 ml) and further stirredfor 6 h. The reaction mixture was diluted with ether and the beigecrystals were collected by filtration, washed with ether and MeOH,affording off-white crystals.

MS (ESI, m/z): 348.07 [M+H⁺] for C₁₅H₂₂N₅O₄; t_(R)=0.38 min (MS2).

17.6.1-cyclopropyl-6-fluoro-4-oxo-7-(4-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-piperidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid

In analogy to Example 2, starting from intermediate 17.5 (166 mg) and7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid (commercial; 100 mg), the title compound was obtained as anoff-white solid.

¹H NMR (DMSO-d₆) δ: 11.17 (s, 1H), 8.59 (s, 1H), 8.04 (d, J=13.6 Hz,1H), 7.58 (d, J=8.7 Hz, 1H), 7.40 (d, J=8.7 Hz, 1H), 4.27 (br., 1H),4.59 (s, 2H), 4.42 (m, 2H), 4.14 (m, 1H), 3.85 (m, 1H), 3.68 (m, 1H),3.28 (m, 2H), 2.93 (m, 3H), 2.00 (m, 3H), 1.40 (m, 2H), 1.12 (m, 4H). MS(ESI, m/z): 594.09 [M+H⁺] for C₂₈H₂₈N₇O₇F; t_(R)=0.64 min (MS2).

Example 181-cyclopropyl-6-fluoro-4-oxo-7-{4-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-piperazin-1-yl}-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid 18.1.4-((S)-3-benzyloxycarbonylamino-2-hydroxy-propyl)-piperazine-1-carboxylicacid tert-butyl ester

The compound was prepared in analogy to Example 17, step 17.1, startingfrom 1-Boc-piperazine (20.41 g) and [(2S)-oxiranylmethyl]-carbamic acidbenzyl ester (22.75 g). A yellowish oil (16.0 g; 37% yield) wasobtained.

MS (ESI, m/z): 394.12 [M+H⁺] for C₂₀H₃₁N₃O₅; t_(R)=0.67 min (MS2).

18.2. 4-((S)-2-oxo-oxazolidin-5-ylmethyl)-piperazine-1-carboxylic acidtert-butyl ester

The compound was prepared in analogy to Example 17, step 17.2, startingfrom intermediate 18.1 (16.0 g). A colourless solid (5.11 g; 44% yield)was obtained.

MS (ESI, m/z): 259.22 [M-CO] for C₁₃H₂₃N₃O₄; t_(R)=0.68 min (MS2).

18.3.4-[(R)-3-(5-ethoxycarbonylmethoxy-6-nitro-pyridin-2-yl)-2-oxo-oxazolidin-5-ylmethyl]-piperazine-1-carboxylicacid tert-butyl ester

The compound was prepared in analogy to Example 17, step 17.3, startingfrom intermediate 18.2 (6.44 g) and ethyl(6-bromo-2-nitropyridin-3-yloxy)acetate (6.22 g; prepared as describedin WO 2007/118130). A beige foam (9.71 g; 93.5% yield) was obtained.

MS (ESI, m/z): 510.15 [M+H⁺] for C₂₂H₃₁N₅O₉; t_(R)=0.70 min (MS2).

18.4.4-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-piperazine-1-carboxylicacid tert-butyl ester

The compound was prepared in analogy to Example 17, step 17.4, startingfrom intermediate 18.3 (9.71 g). A beige solid (6.27 g; 75.9% yield) wasobtained.

MS (ESI, m/z): 434.03 [M+H⁺] for C₂₀H₂₇N₅O₆; t_(R)=0.59 min (MS2).

18.5.6-((R)-2-oxo-S-piperazin-1-ylmethyl-oxazolidin-3-yl)-4H-pyrido[3,2-b][1,4]oxazin-3-one

The compound was prepared in analogy to Example 17, step 17.5, startingfrom intermediate 18.4 (579 mg). A yellow solid (130 mg; 29% yield) wasobtained.

MS (ESI, m/z): 334.04 [M+H⁺] for C₁₅H₁₉N₅O₄; t_(R)=0.45 min (MS2).

18.6.1-cyclopropyl-6-fluoro-4-oxo-7-{4-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-piperazin-1-yl}-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid

In analogy to Example 2, starting from intermediate 18.5 (117 mg) and7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid (commercial; 90 mg), the title compound was obtained as anoff-white solid (80 mg; 43.3% yield).

¹H NMR (DMSO-d₆) δ: 11.17 (s, 1H), 8.59 (s, 1H), 8.06 (d, J=13.8 Hz,1H), 7.59 (d, J=8.8 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 4.87 (m, 1H), 4.59(s, 2H), 4.20 (m, 1H), 3.82 (m, 5H), 3.69 (m, 1H), 2.70 (m, 6H), 1.13(m, 4H). MS (ESI, m/z): 580.07 [M+H⁺] for C₂₇H₂₆N₇O₇F; t_(R)=0.62 min(MS2).

Example 191-cyclopropyl-6-fluoro-4-oxo-7-{4-[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-piperazin-1-yl}-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid 19.1.6-*(S)-2-oxo-5-piperazin-1-ylmethyl-oxazolidin-3-yl)-4H-pyrido[3,2-b][1,4]oxazin-3-one

The compound was prepared in analogy to steps 18.1 to 18.5 of Example18, starting from [(2R)-oxiranylmethyl]-carbamic acid benzyl ester. Therespective yields for the 5 steps were the following: 59% (yellowishoil; epoxide opening), 28% (colourless solid; oxazolidinone formation),23% (brown oil; arylation), 59% (beige solid; oxazinone formation) and99% (beige solid; HCl treatment).

MS (ESI, m/z): 334.04 [M+H⁺] for C₁₅H₁₉N₅O₄; t_(R)=0.45 min (MS2).

19.2.1-cyclopropyl-6-fluoro-4-oxo-7-{4-[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-piperazin-1-yl}-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid

In analogy to Example 18, step 18.6, starting from intermediate 19.1(101 mg) and7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid (commercial; 77 mg), the title compound was obtained as a beigesolid (130 mg; 82% yield).

¹H NMR (DMSO-d₆) δ: 11.17 (s, 1H); 8.59 (s, 1H); 8.06 (d, J=13.8 Hz,1H); 7.59 (d, J=8.8 Hz, 1H); 7.41 (d, J=8.8 Hz, 1H); 4.87 (m, 1H); 4.59(s, 2H); 4.20 (m, 1H); 3.82 (m, 5H); 3.69 (m, 1H); 2.70 (m, 6H); 1.13(m, 4H). MS (ESI, m/z): 580.07 [M+H⁺] for C₂₇H₂₆N₇O₇F; t_(R)=0.62 min(MS2).

Example 201-cyclopropyl-6-fluoro-4-oxo-7-(4-{[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-piperidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid 20.1.6-[(S)-2-oxo-5-(piperidin-4-ylaminomethyl)-oxazolidin-3-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-onedihydrochloride

The compound was prepared in analogy to steps 17.1. to 17.5 of Example17, starting from [(2S)-oxiranylmethyl]-carbamic acid benzyl ester. Therespective yields for the 5 steps were the following: 71% (colourlessoil; epoxide opening), 96% (yellowish oil; carbamate formation), 93%(yellow foam; arylation), 81% (beige solid; cyclisation) and 81% (yellowfoam; HCl treatment).

MS (ESI, m/z): 348.27 [M+H⁺] for C₁₅H₁₉N₅O₄; t_(R)=0.61 min (MS2).

20.2.1-cyclopropyl-6-fluoro-4-oxo-7-(4-{[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-piperidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid

In analogy to Example 17, step 17.6, starting from intermediate 20.1(1.76 g) and7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid (commercial; 1.13 g), the title compound was obtained as a beigesolid (1.05 g; 44% yield).

¹H NMR (DMSO-d₆) δ: 11.17 (s, 1H), 8.59 (s, 1H), 8.04 (d, J=13.6 Hz,1H), 7.58 (d, J=8.7 Hz, 1H), 7.40 (d, J=8.7 Hz, 1H), 4.27 (br., 1H),4.59 (s, 2H), 4.42 (m, 2H), 4.14 (m, 1H), 3.85 (m, 1H), 3.68 (m, 1H),3.28 (m, 2H), 2.93 (m, 3H), 2.00 (m, 3H), 1.40 (m, 2H), 1.12 (m, 4H). MS(ESI, m/z): 594.09 [M+H⁺] for C₂₈H₂₈N₇O₇F; t_(R)=0.63 min (MS2).

Example 211-cyclopropyl-6-fluoro-4-oxo-7-((RS)-3-{[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-pyrrolidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid 21.1.(RS)-3-((S)-3-benzyloxycarbonylamino-2-hydroxy-propylamino)-pyrrolidine-1-carboxylicacid tert-butyl ester

The title compound was prepared in analogy to Example 17, step 17.1,starting from [(2R)-oxiranylmethyl]-carbamic acid benzyl ester (8.23 g;prepared according to WO 2004/002973) and rac-3-amino-1-Boc-pyrrolidine(7.40 g; commercial) in MeCN (300 mL), affording a colourless oil (10.7g; 68% yield).

MS (ESI, m/z): 394.19 [M+H⁺] for C₂₀H₃₁N₃O₅; t_(R)=0.64 min (MS2).

21.2.(RS)-3-[((S)-2-oxo-oxazolidin-5-ylmethyl)-amino]-pyrrolidine-1-carboxylicacid tert-butyl ester

A solution of intermediate 21.1 (10.7 g) in THF (175 mL) was treated at0° C. with KOtBu (3.05 g) and further stirred at rt for 1 h. Thereaction mixture was concentrated in vacuo and the residue was taken upin EA/water. The aq. layer was extracted twice with EA. The combinedorg. layers were washed with brine, dried over MgSO₄, filtered,evaporated and purified by CC (EA/MeOH 19:1 to 9:1+1% NH₄OH), affordinga colourless glass (6.90 g; 89% yield).

MS (ESI, m/z): 331.20 [M+H⁺] for C₁₃H₂₃N₃O₄; t_(R)=0.50 min (MS2).

21.3.(RS)-3-{[(S)-3-(5-ethoxycarbonylmethoxy-6-nitro-pyridin-2-yl)-2-oxo-oxazolidin-5-ylmethyl]-amino}-pyrrolidine-1-carboxylicacid tert-butyl ester

The title compound was prepared in analogy to Example 17, step 17.1,starting from ethyl (6-bromo-2-nitropyridin-3-yloxy)acetate (6.84 g;prepared as described in WO 2007/118130) and intermediate 21.2 (6.4 g),affording a yellowish foam (11.34 g; 99% yield).

MS (ESI, m/z): 454.08 [M+H⁺] for C₂₂H₃₁N₅O₉; t_(R)=0.70 min (MS2).

21.4.(RS)-3-{[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-pyrrolidine-1-carboxylicacid tert-butyl ester

In analogy to Example 17, step 17.4, the title compound was preparedfrom intermediate 21.3 (11.34 g), affording a yellowish foam (7.13 g;74% yield).

MS (ESI, m/z): 434.16 [M+H⁺] for C₂₀H₂₇N₅O₆; t_(R)=0.57 min (MS2).

21.5.6-((S)-2-oxo-5-(((RS)-pyrrolidin-3-ylamino)methyl)oxazolidin-3-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onedihydrochloride

In analogy to Example 17, step 17.5, the title compound was preparedfrom intermediate 21.4 (7.0 g), affording a yellowish solid (6.7 g, 100%yield).

MS (ESI, m/z): 334.22 [M+H⁺] for C₁₅H₂₁N₅O₄Cl₂; t_(R)=0.40 min (MS2).

21.6.1-cyclopropyl-6-fluoro-4-oxo-7-((RS)-3-{[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-pyrrolidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid

In analogy to Example 2, starting from intermediate 21.5 (406 mg) and7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid (commercial; 283 mg), the title compound was obtained as a beigesolid (mixture of diastereomers; 398 mg; 68% yield).

MS (ESI, m/z): 580.07 [M+H⁺] for C₂₇H₂₆N₇O₇F; t_(R)=0.62 min (MS2).

Example 221-cyclopropyl-6-fluoro-4-oxo-7-[(S)-3-({[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-methyl)-pyrrolidin-1-yl]-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid 22.1.(S)-3-[((S)-3-benzyloxycarbonylamino-2-hydroxy-propylamino)-methyl]-pyrrolidine-1-carboxylicacid tert-butyl ester

The title compound was prepared in analogy to Example 17, step 17.1,starting from [(2R)-oxiranylmethyl]-carbamic acid benzyl ester (5.17 g;prepared according to WO 2004/002973) and(S)-3-aminoethylpyrrolidine-1-carboxylic acid tert-butyl ester (5.00 g;commercial) in MeCN (120 mL), affording a colourless oil (6.4 g; 63%yield).

MS (ESI, m/z): 408.21 [M+H⁺] for C₂₁H₃₃N₃O₅; t_(R)=0.66 min (MS2).

22.2.(S)-3-{[((S)-2-oxo-oxazolidin-5-ylmethyl)-amino]-methyl}-pyrrolidine-1-carboxylicacid tert-butyl ester

A solution of intermediate 22.1 (6.4 g) in THF (100 mL) was treated at0° C. with KOtBu (1.76 g) and further stirred at rt for 1 h. Thereaction mixture was concentrated in vacuo and the residue was taken upin EA/water. The aq. layer was extracted twice with EA. The combinedorg. layers were washed with brine, dried over MgSO₄, filtered,evaporated and purified by CC (EA/MeOH 19:1 to 9:1+1% NH₄OH), affordinga colourless oil (4.34 g; 92% yield).

MS (ESI, m/z): 300.17 [M+H⁺] for C₁₄H₂₅N₃O₄; t_(R)=0.50 min (MS2).

22.3.(S)-3-({[(S)-3-(5-ethoxycarbonylmethoxy-6-nitro-pyridin-2-yl)-2-oxo-oxazolidin-5-ylmethyl]-amino}-methyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

The title compound was prepared in analogy to Example 17, step 17.3,starting from ethyl (6-bromo-2-nitropyridin-3-yloxy)acetate (4.01 g;prepared according to WO 2007/118130) and intermediate 22.2 (3.94 g),affording a yellowish foam (7.01 g; 100% yield).

MS (ESI, m/z): 524.22 [M+H⁺] for C₂₃H₃₃N₅O₉; t_(R)=0.71 min (MS2).

22.4.(S)-3-({[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-methyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

In analogy to Example 17, step 17.4, the title compound was preparedfrom intermediate 22.3 (7.01 g), affording a yellowish foam (4.1 g; 68%yield).

MS (ESI, m/z): 448.18 [M+H⁺] for C₂₁H₂₉N₅O₆; t_(R)=0.61 min (MS2).

22.5.6-((S)-2-oxo-5-{[((R)-1-pyrrolidin-3-ylmethyl)-amino]-methyl}-oxazolidin-3-yl)-4H-pyrido[3,2-b][1,4]oxazin-3-onedihydrochloride

In analogy to Example 17, step 17.5, the title compound was preparedfrom intermediate 22.4 (4.0 g), affording a colourless solid (3.87 g;100% yield).

MS (ESI, m/z): 348.26 [M+H⁺] for C₁₆H₂₃N₅O₄Cl₂; t_(R)=0.40 min (MS2).

22.6.1-cyclopropyl-6-fluoro-4-oxo-7-[(S)-3-({[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-methyl)-pyrrolidin-1-yl]-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid

In analogy to Example 2, starting from intermediate 22.5 (420 mg) and7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid (commercial; 283 mg), the title compound was obtained as a beigesolid (440 mg; 74% yield).

¹H NMR (DMSO-d₆) δ: 11.15 (s, 1H), 8.52 (s, 1H), 7.91 (d, J=12.7 Hz,1H), 7.57 (d, J=8.7 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H), 4.77 (br., 1H),4.59 (s, 2H), 4.14 (m, 1H), 3.77 (m, 6H), 2.95 (m, 2H), 2.94 (m, 2H),2.73 (m, 2H), 2.05 (s, 1H), 1.85 (m, 1H), 1.09 (m, 4H). MS (ESI, m/z):594.06 [M+H⁺] for C₂₈H₂₈N₇O₇F; t_(R)=0.64 min (MS2).

Example 239-cyclopropyl-6-fluoro-3-hydroxy-7-(4-{[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-piperidin-1-yl)-9H-1-thia-2,8,9-triaza-cyclopenta[b]naphthalen-4-one

In analogy to Example 2, starting from intermediate 20.1 (151 mg) and7-chloro-9-cyclopropyl-6-fluoro-isothiazolo[5,4-b][1,8]naphthyridine-3,4(2H,9H)-dione(93 mg; prepared according to Chu et al., J. Heterocycl. Chem. (1990),27(5), 1191-1195), the title compound was obtained as a beige solid (110mg; 59% yield).

¹H NMR (DMSO-d₆) δ: 11.16 (s, 1H), 7.89 (d, J=12.7 Hz, 1H), 7.58 (d,J=8.7 Hz, 1H), 7.40 (d, J=8.7 Hz, 1H), 4.68 (m, 1H), 4.58 (s, 2H), 4.33(m, 2H), 4.11 (m, 1H), 3.86 (m, 1H), 3.27 (m, 5H), 2.88 (d, J=5.2 Hz,2H), 2.76 (m, 1H), 1.95 (m, 2H), 1.36 (m, 2H), 1.17 (m, 4H). MS (ESI,m/z): 622.98 [M+H⁺] for C₂₈H₂₇N₈O₆FS; t_(R)=0.61 min (MS2).

Example 249-cyclopropyl-6-fluoro-3-hydroxy-7-(3-{[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-9H-1-thia-2,8,9-triaza-cyclopenta[b]naphthalen-4-one

In analogy to Example 2, starting from6-[(5S)-5-[(3-azetidinylamino)methyl]-2-oxo-3-oxazolidinyl]-2H-1,4-benzoxazin-3(4H)-one(prepared in analogy to WO 2008/126034; 128 mg) and7-chloro-9-cyclopropyl-6-fluoro-isothiazolo[5,4-b][1,8]naphthyridine-3,4(2H,9H)-dione(93 mg; prepared according to Chu et al., J. Heterocycl. Chem. (1990),27(5), 1191-1195), the title compound was obtained as a beige solid (100mg; 56% yield).

¹H NMR (DMSO-d₆) δ: 7.83 (d, J=11.7 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H),7.40 (d,

J=8.6 Hz, 1H), 4.71 (m, 1H), 4.59 (s, 2H), 4.41 (m, 2H), 4.14 (m, 1H),4.01 (m, 2H), 3.84 (m, 2H), 3.32 (m, 8H), 2.87 (m, 2H), 1.16 (m, 4H). MS(ESI, m/z): 594.88 [M+H⁺] for C₂₆H₂₃N₈O₆FS; t_(R)=0.58 min (MS2).

Example 259-cyclopropyl-6-fluoro-3-hydroxy-7-{4-[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-piperazin-1-yl}-9H-1-thia-2,8,9-triaza-cyclopenta[b]naphthalen-4-one

In analogy to Example 2, starting from6-((S)-2-oxo-5-piperazin-1-ylmethyl-oxazolidin-3-yl)-4H-pyrido[3,2-b][1,4]oxazin-3-one(intermediate 19.1; 133 mg) and7-chloro-9-cyclopropyl-6-fluoro-isothiazolo[5,4-b][1,8]naphthyridine-3,4(2H,9H)-dione(93 mg; prepared according to Chu et al., J. Heterocycl. Chem. (1990),27(5), 1191-1195), the title compound was obtained as a beige solid (90mg; 49% yield).

¹H NMR (DMSO-d₆) δ: 11.23 (s, 1H), 8.03 (d, J=13.2 Hz, 1H), 7.57 (m,1H), 7.43 (m, 1H), 4.61 (s, 2H), 4.55 (m, 2H), 4.29 (m, 1H), 3.54 (m,10H), 1.21 (m, 4H).

MS (ESI, m/z): 608.97 [M+H⁺] for C₂₇H₂₅N₈O₆FS; t_(R)=0.59 min (MS2).

Pharmacological Properties of the Invention Compounds In Vitro AssaysBacterial Growth Minimal Inhibitory Concentrations: ExperimentalMethods:

Minimal inhibitory concentrations (MICs; mg/l) were determined incation-adjusted Mueller-Hinton Broth by a microdilution method followingthe description given in “Methods for Dilution AntimicrobialSusceptibility Tests for Bacteria that Grow Aerobically”, Approvedstandard, 7^(th) ed., Clinical and Laboratory Standards Institute (CLSI)Document M7-A7, Wayne, Pa., USA, 2006.

All Example compounds were tested against several Gram positive and Gramnegative bacteria. Typical antibacterial test results are given in thetable hereafter (MIC in mg/l). Staphylococcus aureus A798 andAcinetobacter baumanii T6474 are multiply-resistant strains, inparticular quinolone resistant.

MIC for MIC for MIC for MIC for Example S. aureus A. baumanii Example S.aureus A. baumanii No. A798 T6474 No. A798 T6474 1 ≦0.016 0.125 2 ≦0.0160.125 3 ≦0.016 0.063 4 ≦0.016 0.125 5 ≦0.016 1 6 ≦0.016 0.031 7 0.0630.25 8 0.063 0.25 9 0.063 0.06 10 0.063 0.25 11 0.063 0.063 12 ≦0.016≦0.016 13 ≦0.016 1 14 0.031 0.06 15 0.25 4 16 ≦0.016 0.125 17 ≦0.016≦0.016 18 0.031 0.25 19 ≦0.016 0.063 20 ≦0.016 ≦0.016 21 0.125 0.25 220.125 0.031 23 ≦0.016 ≦0.016 24 ≦0.016 0.063 25 ≦0.016 0.125 Cipro >32>32

1. A compound of formula I

wherein R^(1a) represents H or carboxy and R^(1b) represents H, orR^(1a) and R^(1b) represent together either the group *—C(O)—NH—S—^(#)or the group *—C(OH)═N—S—^(#) wherein “*” represents the point ofattachment of R^(1a) and “^(#)” represents the point of attachment ofR^(1b); R² represents H, (C₁-C₃)alkyl, hydroxy-(C₁-C₃)alkyl, benzyl or(C₃-C₅)cycloalkyl; R³ represents H or halogen; U represents N or CR⁴;wherein R⁴ is H or (C₁-C₃)alkoxy; A represents CH, B represents NH, mrepresents 1 or 2 and n represents 1 or 2; or A represents N, B isabsent, m represents 2 and n represents 2; Y represents CH or N; and Qrepresents O or S; or a salt of such a compound.
 2. The compoundaccording to claim 1, wherein: R^(1a) represents H or carboxy; R^(1b)represents H; and A represents CH, B represents NH and m represents 1and n represents 1 or m represents 2 and n represents 2; or A representsN, B is absent, m represents 2 and n represents 2; or a salt of such acompound.
 3. The compound according to claim 1, wherein R¹ representscarboxy; or a salt of such a compound.
 4. The compound according toclaim 1, wherein R² represents (C₁-C₃)alkyl or (C₃-C₅)cycloalkyl; or asalt of such a compound.
 5. The compound according to claim 4, whereinR² represents cyclopropyl; or a salt of such a compound.
 6. The compoundaccording to claim 1, wherein R³ represents halogen; or a salt of such acompound.
 7. The compound according to claim 1, wherein U represents N;or a salt of such a compound.
 8. The compound according to claim 1,wherein U represents CR⁴, wherein R⁴ is H or (C1-C3)alkoxy; or a salt ofsuch a compound.
 9. The compound according to claim 1, wherein the group

is selected from wherein the asterisks denote the bond linking saidgroup to the CH₂ group which is attached to the oxazolidinone moiety; ora salt of such a compound.
 10. The compound according to claim 1,wherein Y represents CH or N and Q represents O, or Y represents CH andQ represents S; or a salt of such a compound.
 11. The compound accordingto claim 1, wherein: R^(1a) represents carboxy and R^(1b) represents H,or R^(1a) and R^(1b) represent together either the group*—C(O)—NH—S—^(#) or the group *—C(OH)═N—S—^(#) wherein “*” representsthe point of attachment of R^(1a) and “^(#)” represents the point ofattachment of R^(1b); R² represents cyclopropyl; R³ represents fluorine;U represents N; A represents CH, B represents NH, m represents 1 or 2and n represents 1 or 2; Y represents N; and Q represents O; or a saltof such a compound.
 12. The compound according to claim 1, wherein thecompound is:1-cyclopropyl-6-fluoro-4-oxo-7-{4-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]-piperazin-1-yl}-1,4-dihydro-quinoline-3-carboxylicacid;1-cyclopropyl-6-fluoro-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid;1-cyclopropyl-6-fluoro-4-oxo-7-{4-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]-piperazin-1-yl}-1,4-dihydro-quinoline-3-carboxylicacid;1-cyclopropyl-6-fluoro-4-oxo-7-{4-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]-piperazin-1-yl}-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid;6-((R)-5-{[1-(8-cyclopropyl-3-fluoro-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-yl)-azetidin-3-ylamino]-methyl}-2-oxo-oxazolidin-3-yl)-4H-benzo[1,4]thiazin-3-one;1-cyclopropyl-6-fluoro-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid;1-cyclopropyl-8-methoxy-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-quinoline-3-carboxylicacid;1-cyclopropyl-8-methoxy-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-quinoline-3-carboxylicacid;1-ethyl-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid;1-cyclopropyl-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid;1-methyl-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid;6-fluoro-1-methyl-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid;1-benzyl-6-fluoro-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid;1-cyclopropyl-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid;6-fluoro-1-(2-hydroxy-ethyl)-4-oxo-7-(3-{[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid;1-cyclopropyl-6-fluoro-4-oxo-7-{4-[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl]-piperazin-1-yl}-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid;1-cyclopropyl-6-fluoro-4-oxo-7-{4-[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-piperidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid;1-cyclopropyl-6-fluoro-4-oxo-7-{4-[(R)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-piperazin-1-yl}-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid;1-cyclopropyl-6-fluoro-4-oxo-7-{4-[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-piperazin-1-yl}-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid;1-cyclopropyl-6-fluoro-4-oxo-7-(4-{[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-piperidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid;1-cyclopropyl-6-fluoro-4-oxo-7-(3-{[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-pyrrolidin-1-yl)-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid;1-cyclopropyl-6-fluoro-4-oxo-7-[(S)-3-({[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-methyl)-pyrrolidin-1-yl]-1,4-dihydro-[1,8]naphthyridine-3-carboxylicacid;9-cyclopropyl-6-fluoro-3-hydroxy-7-(4-{[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-piperidin-1-yl)-9H-1-thia-2,8,9-triaza-cyclopenta[b]naphthalen-4-one;9-cyclopropyl-6-fluoro-3-hydroxy-7-(3-{[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-amino}-azetidin-1-yl)-9H-1-thia-2,8,9-triaza-cyclopenta[b]naphthalen-4-one;or9-cyclopropyl-6-fluoro-3-hydroxy-7-{4-[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-oxazolidin-5-ylmethyl]-piperazin-1-yl}-9H-1-thia-2,8,9-triaza-cyclopenta[b]naphthalen-4-one;or a salt of such a compound.
 13. A medicament comprising the compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof. 14.A pharmaceutical composition comprising, as active principle, thecompound according to claim 1, or a pharmaceutically acceptable saltthereof, and at least one therapeutically inert excipient.
 15. A methodof treating or preventing a bacterial infection comprising administeringan effective amount of the composition or a salt thereof according toclaim 1 to a subject in need thereof.
 16. A method of treating orpreventing a bacterial infection comprising administering an effectiveamount of the pharmaceutical composition or a salt thereof according toclaim 14 to a subject in need thereof.